MICE LEttEr Summer 2011

MICE LetterSummer 2011

C O N t E N t

Scientific Highlights p. 1– 3•Compartimentalization of Autoimmune Responses

• Intrinsic Antiviral Immunity

News and Updates p. 4 – 5•Research Training Group 1660: Network Meeting 2011

•Research Training Group 1071: Annual Retreat 2011

•m4 Award

Upcoming Events p. 6 •MICE Immunological Colloquium – Preview Winter 2011/2012

•Conferences (Co-)Organized by MICE Members

•Further Conferences of Interest

5 MICE LEttEr Summer 2011 6 Summer 2011

Factors leading to the development

of immune responses against specific antigens

in an organ-specific manner remain

largely unknown

The suppression of CD101 expression

promotes the severe liver autoimmunity in NOD.B6 Cd101

mice

Triplebodies which... efficiently mediate

killing of AML stem cells by NK cells

Compartimentalization of Autoimmune responses

Infection Converts Protec tive Alleles for Type 1 Diabetes into Susceptibility Alleles for Primary Biliary Cirrhosis

Jochen mattner InStItute of mIcrobIology

autoimmune diseases are driven by complex interactions of environmental factors with genetic traits. although autoimmune genes often cluster together in defined patient populations that are prone to the development of autoimmune disease, the factors leading to the development of immune responses against specific antigens in an organ-specific manner remain largely unknown. utililizing noD congenic mice as model, we describe that introgression of the Cd101 allele encoding the negative costimulatory molecule cD101 from b6 mice onto the noD background protects mice from the development of spontaneous type 1 diabetes (t1D); when infected, however, with an ubiquitous alphaproteo -bacterium, noD mice carrying the b6 Cd101 allele (noD.b6 Cd101) are prone to develop severe liver autoimmunity resembling primary biliary cirrhosis (Pbc) in humans. In contrast to the enhanced expression of cD101 on regulatory t cells in naïve noD.b6 Cd101 mice that may contribute to the protection from t1D, infection triggers a downregulation of cD101 on Dcs and granulocytes correlating with more severe liver disease in noD.b6 Cd101 mice compared to noD mice. While the suppression of cD101 expression on Dcs promotes a hyperreactive t cell response, downregulation of cD101 on granulocytes affects their recruitment to the liver prolonging bacterial persistence. Infection of cD101 knockout mice results in more severe liver disease compared to wild-type mice sug-gesting that the suppression of cD101 expres-sion promotes the severe liver autoimmunity in noD.b6 Cd101 mice. thus, allelic variations alter the susceptibility of individuals not only to

Scientific HigHligHtS

NEws ANd UpdAtEs

Prof. Dr. georg fey, Division of genetics, Depart- ment of biology from the university of erlangen- nuremberg, has been awarded the m4 award of the bavarian ministry of economic affairs, Infrastructure, transport and technology, and the federal ministry of education and research together with his cooperation partners Prof. Dr. Karl-Peter hopfner (gene center of the uni-versity of munich – lmu) and PD Dr. Dr. fuat oduncu (university hospital of the university of munich - lmu). they have developed triple-bodies which recognize two antigens on acute myeloid leukemia (aml) stem cells and cD16 on natural Killer (nK) cells and thereby effi-

ciently mediate killing of aml stem cells by nK cells. their project will be funded with € 500,000 over the next two years and has high relevance for the personalized treatment of acute myeloid leukemia. the researchers have founded the company Spectramab, a spin-off from the univer-sity of erlangen-nuremberg located in martinsried near munich, with the objective to bring the triple-bodies with the ability to eliminate cancer stem cells to clinical application. the m4 award aims at supporting research projects committed to the development of new therapeutic approaches and techniques in the field of personalized medi-cine with a high economic potential.

A successful team: PD Dr. Dr. Oduncu, Prof. Dr. Fey (CSO SpectraMab), Prof. Dr. Jacob (CEO SpectraMab), and Prof. Dr. Hopfner ( from left to right )

m4 AwArD

research Team from the University of Erlangen-Nuremberg and the Ludwig-Maximilians-University Munich recieves Grant for Leukemia research 18.10. 2011

To be announced

25.10. 2011

Andreas Diefenbach freiburg

Development and Function

of Innate Lymphocytes

08.11.2011

Francesca Granucci milan, Italy

The Multifaceted Roles

of CD14 in Innate Immunity

15.11.2011

Eicke Latz bonn

Mechanisms of Inflam-

masome Activation in

Inflammatory Diseases

22.11. 2011

Manolis Pasparakis cologne

Epithelial Regulation

of Intestinal Inflammation

and Cancer

29.11. 2011

Christopher D. Gregory edinburgh, uK

The Role of Apoptosis

in Conditioning the Micro-

environment of Tumours

06.12.2011

Michael Sixt Klosterneuburg, austria

Mechanisms of Leukocyte

Chemotaxis

Special Lecture on Monday12.12. 2011

Kenneth Murphy St. louis, uSa

Title to be announced

20.12. 2011

To be announced

10.01.2012

To be announced

17.01. 2012

Ofer Mandelboim Jerusalem, Israel

Proteins and miRNA-

mediated Regulation

of NK Cell Activity

24.01. 2012

robert M. Strietercharlottesville, uSa

The Role of CXC Chemo-

kines in Lung Cancer

31.01. 2012

Tariq Enver london, uK

Title to be announced

07.02. 2012

To be announced

UpCOMINg EvENts

MICE Immunological Colloquium – Preview winter 2011/2012

Conferences (Co-)organized by MICE members

October 2 – 4, 2011

1st International SFB 796 Conference: Mechanisms of viral host cell manipulation: From plants to humansbamberg

www.sfb796.de

October 9– 14, 2011

3rd Autumn School

“Current Concepts

in Immunology” of

the German Society

of Immunology bad Schandau

www.herbstschule.de

Further Conferences of Interest

October 3 – 4, 2011

5th International

Vilnius Course

“Update on Paediatric

Infectious Diseases”Vilnius, lithuaniawww.vilniuscourse.com

March 18 – 21, 2012

world Immune

regulation

Meeting-VIDavos, Switzerlandwww.wirm.ch

Publishermedical Immunology campus erlangen

Schlossgarten 4 | 91054 erlangen

Phone +49.9131.85.2 67 84 Fax +49.9131.85.2 21 01

www.mice.uni-erlangen.de

Conceptual Design and EditorDr. annette grohmann V.i.S.d.P.

Subscription via Email to:aegrohma@viro.med.uni-erlangen.de

Please note that the authors are responsible for the content of their contributions.

We are looking forward to suggestions for the next mIce letter.

Please send material to:aegrohma@viro.med.uni-erlangen.de

Intrinsic Antiviral Immunity:

Nuclear Dot Proteins as a Cellular Defense against Herpesviruses

thomaS StammInger · nIna taValaI InStItute of clInIcal anD molecular VIrology

research of the last years has revealed that micro-bial infections are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors which give cells the capacity to resist pathogens. unlike the innate and adaptive part of the immune system, that require pathogen-induced signaling cascades in order to be switched on, these so-called intrinsic immune mechanisms are mediated by cellular proteins that are constitu-tively expressed and active before a pathogen enters the cell, thus serving as a front-line defense. components of the intrinsic immunity have first been identified in the context of viral infections when it became apparent that cellular host factors like aPobec enzymes or the tripartite motif protein trIm5-alpha can confer resistance to retroviral infections and thus are able to affect viral tropism.

MICE LEttEr Summer 2011 2

Scientific HigHligHtS Scientific HigHligHtS

3

autoimmune disease in general, but may also contribute in which tissue they manifest. under-standing the regulation of these genes while being exposed to different environmental factors may help us to understand the regulation of autoimmune genes in general and to define novel genetic targets for immune-intervention.

Mohammed JP, Fusakio ME, Rainbow DB, Moule C, Fraser HI, Clark J, Todd JA, Peterson LB, Savage PB, Wills-Karp M, Ridgway WM, Wicker LS, Mattner J.

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans- Induced Liver Autoimmunity. J Immunol. 2011; 187(1):337–4

Rainbow DB, Moule C, Fraser HI, Clark J, Howlett SK, Burren O, Christensen M, Moody V, Steward CA, Mohammed JP, Fusakio ME, Masteller EL, Finger EB, Houchins JP, Naf D, Koentgen F, Ridgway WM, Todd JA, Bluestone JA, Peterson LB, Mattner J, Wicker LS.

Evidence that Cd101 Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice. J Immunol. 2011; 187(1):325–36

Compartimentalization of Autoimmune responsesJochen mattner InStItute of mIcrobIology

C O N t I N U E d f r O M pA g E 1

Cd101 alleles regulate the resistance and susceptibility to liver disease induced by N. aro-infection. expression of the noD Cd101 allele induces a more tolerogenic milieu in the liver by promoting treg responses whereas expression of the b6 Cd101 allele triggers an overzealouos t cell response upon infection with N. aro. the loss of cD101 expression on Dcs drives the enhanced Ifn-γ and Il-17 production by t cells and subsequently the induction of liver disease upon N. aro-infection.

our laboratory has investigated, whether a subnu-clear structure, termed nuclear domain 10 (nD10), contributes to the resistance of cells against her-pesvirus infections. nD10, alternatively termed Pml nuclear bodies, are dot-like structures of the cell nucleus, that are defined by the distinct accumula-tion of specific cellular proteins like Pml, hDaxx and Sp100. approximately 15 years ago, it was detected that herpesviral Dna associates with these protein accumulations within the nucleus, however, the functional significance of this juxtapo-sition was not clear. by establishing primary human fibroblasts with an rna-interference mediated depletion of the major nD10 proteins Pml, Sp100 or hDaxx we could show, that these proteins act as cellular restriction factors by inducing a silencing of viral gene expression. moreover, our research revealed that specific viral proteins are able to an-tagonize this cellular silencing mechanism. this establishes a delicate balance between cellular defense and viral antagonism which determines whether the herpesvirus enters the productive re p-lication cycle or the latency program.

Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T. Evidence for a dual antiviral role of the major ND10 component Sp100 during the immediate-early and late phase of the human cytomegalovirus replication cycle. J. Virol. 2011, Jul 2 [Ebup ahead of print]

Adler M, Tavalai N, Müller R, Stamminger T. Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100. J. Gen.Virol. 2011; 92:1532–8.

Tavalai N, Stamminger T. Instrinsic cellular defense mechanisms targeting cytomegalovirus.Virus Res. 2011; 157:128–33.

Antagonization of nuclear domain 10 (ND10)-mediated repression by cytomegalovirus (HCMV) infection. Subpanels a-d: intact nD10 (as detected by indirect immunofluorescence analysis using a monoclonal antibody against the Pml protein) in non-infected primary human fibroblasts; nD10 are defined as accumulations of specific cellular proteins like Pml, Sp100 and hDaxx. Subpanels e-h: nD10 are disrupted by infection of fibroblasts with cytomegalovirus (hcmV). DaPI: detection of the nucleus. Intact nD10 are able to induce a silencing of viral genomes. this cellular repression mechanism is antagonized by specific viral proteins, leading to productive viral replication.

Microbial infec-tions are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors

PML, Sp100 and hDaxx … act as cellular restriction factors by inducing a silencing of viral gene expression

A delicate balance between cellular defense and viral antagonism

Allelic variations alter the suscepti-

bility of individuals not only to auto-immune disease

in general, but may also contribute

in which tissue they manifest

MICE LEttEr Summer 2011 4

rESEArCH TrAINING GrOUP 1071: ANNUAL rETrEAT 2011

10th retreat of the research Training Group GrK 1071 in Schlaifhausen with Participation of the Harvard PhD Students and Faculty Members

the 10th retreat of the Dfg (german research foundation) research training group grK 1071 “Viruses of the Immune System” was held in Schlaifhausen from 23 to 24 may 2011. the meeting was organized by PhD students Jenny eckardt, tanja bräu, Silke tudor, and Sebastian bolduan and hosted 25 doc toral students from erlangen and six doctoral students from harvard, all members of the research training group, as well as 16 research group leaders from erlangen and six faculty members from harvard involved in the program. In addition, interested scientists from the participating research groups joined the retreat, which provided to the doctoral students an excellent opportunity to present their data to a selected audience and discuss their results in a relaxed atmosphere. this year, the organizers were happy to wel- come Prof. Dr. otto haller from freiburg as a guest speaker, who gave a talk on “host restriction factors: molecular in-sights into the antiviral functions of mx gtPases”. a further

highlight of the retreat was the award of the golden mic, presented to thomas Sommermann for his talk on “you’re either in or out – the nfκb pathway controls glucose trans-port in lymphocytes”. the Presentation award golden mic aims to honor “the most noteworthy presentation given by a student” at the retreat, who is elected by the audience. the participants agreed that the 2011 retreat was again a valuable platform for scientific exchange, practicing presen-tation skills, and getting together with PhD students and scientists from different research groups in an enjoyable scientific environment.

from 6 to 8 June 2011, the annual retreat of the network of three immunology research training groups of the Dfg (german research foundation) was held at Klosterhospiz neresheim and organized by the grK 520 (Würzburg). the network interconnects the Integrated research training group of the collaborative research centre Sfb 685 (Immuno -therapy, tübingen), the research training group grK 520 (Immunomodulation, Würzburg), and the erlangen research

rESEArCH TrAINING GrOUP 1660: NETwOrK MEETING 2011

Annual Joint retreat of the research Training Groups GrK 1660 (Erlangen), GrK 520 (würzburg) and the Inte grat ed research Training Group (IrTG) of the SFB 685 (Tübingen)

training group 1660 (adaptive Immunity). the annual re treat provides an excellent platform for doctoral students and proj-ect leaders to present their data and to discuss their research. It has been well established and become an integral part on the agenda of the network for over ten years. eight doctoral students of each research training group gave an oral presen-tation. all participants had the opportunity to present a poster on their results. this year, the fast track doctoral students from the erlangen grK 1660 – a pilot project for a doctoral fast track program from bachelor to PhD – were involved for the first time and impressively presented the results from their first-year lab rotations. likewise, the associated members and mD students of the grK 1660 successfully participated in the meeting. overall, the annual retreat was a great success and contributed once more to the scientific exchange within the network.

NEws ANd UpdAtEs

… ready for the welcome address Guest speaker Prof. Dr. Otto Haller

Participants of the Network Meeting 2011

Intrinsic Antiviral Immunity:

Nuclear Dot Proteins as a Cellular Defense against Herpesviruses

thomaS StammInger · nIna taValaI InStItute of clInIcal anD molecular VIrology

research of the last years has revealed that micro-bial infections are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors which give cells the capacity to resist pathogens. unlike the innate and adaptive part of the immune system, that require pathogen-induced signaling cascades in order to be switched on, these so-called intrinsic immune mechanisms are mediated by cellular proteins that are constitu-tively expressed and active before a pathogen enters the cell, thus serving as a front-line defense. components of the intrinsic immunity have first been identified in the context of viral infections when it became apparent that cellular host factors like aPobec enzymes or the tripartite motif protein trIm5-alpha can confer resistance to retroviral infections and thus are able to affect viral tropism.

MICE LEttEr Summer 2011 2

Scientific HigHligHtS Scientific HigHligHtS

3

autoimmune disease in general, but may also contribute in which tissue they manifest. under-standing the regulation of these genes while being exposed to different environmental factors may help us to understand the regulation of autoimmune genes in general and to define novel genetic targets for immune-intervention.

Mohammed JP, Fusakio ME, Rainbow DB, Moule C, Fraser HI, Clark J, Todd JA, Peterson LB, Savage PB, Wills-Karp M, Ridgway WM, Wicker LS, Mattner J.

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans- Induced Liver Autoimmunity. J Immunol. 2011; 187(1):337–4

Rainbow DB, Moule C, Fraser HI, Clark J, Howlett SK, Burren O, Christensen M, Moody V, Steward CA, Mohammed JP, Fusakio ME, Masteller EL, Finger EB, Houchins JP, Naf D, Koentgen F, Ridgway WM, Todd JA, Bluestone JA, Peterson LB, Mattner J, Wicker LS.

Evidence that Cd101 Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice. J Immunol. 2011; 187(1):325–36

Compartimentalization of Autoimmune responsesJochen mattner InStItute of mIcrobIology

C O N t I N U E d f r O M pA g E 1

Cd101 alleles regulate the resistance and susceptibility to liver disease induced by N. aro-infection. expression of the noD Cd101 allele induces a more tolerogenic milieu in the liver by promoting treg responses whereas expression of the b6 Cd101 allele triggers an overzealouos t cell response upon infection with N. aro. the loss of cD101 expression on Dcs drives the enhanced Ifn-γ and Il-17 production by t cells and subsequently the induction of liver disease upon N. aro-infection.

our laboratory has investigated, whether a subnu-clear structure, termed nuclear domain 10 (nD10), contributes to the resistance of cells against her-pesvirus infections. nD10, alternatively termed Pml nuclear bodies, are dot-like structures of the cell nucleus, that are defined by the distinct accumula-tion of specific cellular proteins like Pml, hDaxx and Sp100. approximately 15 years ago, it was detected that herpesviral Dna associates with these protein accumulations within the nucleus, however, the functional significance of this juxtapo-sition was not clear. by establishing primary human fibroblasts with an rna-interference mediated depletion of the major nD10 proteins Pml, Sp100 or hDaxx we could show, that these proteins act as cellular restriction factors by inducing a silencing of viral gene expression. moreover, our research revealed that specific viral proteins are able to an-tagonize this cellular silencing mechanism. this establishes a delicate balance between cellular defense and viral antagonism which determines whether the herpesvirus enters the productive re p-lication cycle or the latency program.

Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T. Evidence for a dual antiviral role of the major ND10 component Sp100 during the immediate-early and late phase of the human cytomegalovirus replication cycle. J. Virol. 2011, Jul 2 [Ebup ahead of print]

Adler M, Tavalai N, Müller R, Stamminger T. Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100. J. Gen.Virol. 2011; 92:1532–8.

Tavalai N, Stamminger T. Instrinsic cellular defense mechanisms targeting cytomegalovirus.Virus Res. 2011; 157:128–33.

Antagonization of nuclear domain 10 (ND10)-mediated repression by cytomegalovirus (HCMV) infection. Subpanels a-d: intact nD10 (as detected by indirect immunofluorescence analysis using a monoclonal antibody against the Pml protein) in non-infected primary human fibroblasts; nD10 are defined as accumulations of specific cellular proteins like Pml, Sp100 and hDaxx. Subpanels e-h: nD10 are disrupted by infection of fibroblasts with cytomegalovirus (hcmV). DaPI: detection of the nucleus. Intact nD10 are able to induce a silencing of viral genomes. this cellular repression mechanism is antagonized by specific viral proteins, leading to productive viral replication.

Microbial infec-tions are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors

PML, Sp100 and hDaxx … act as cellular restriction factors by inducing a silencing of viral gene expression

A delicate balance between cellular defense and viral antagonism

Allelic variations alter the suscepti-

bility of individuals not only to auto-immune disease

in general, but may also contribute

in which tissue they manifest

MICE LEttEr Summer 2011 4

rESEArCH TrAINING GrOUP 1071: ANNUAL rETrEAT 2011

10th retreat of the research Training Group GrK 1071 in Schlaifhausen with Participation of the Harvard PhD Students and Faculty Members

the 10th retreat of the Dfg (german research foundation) research training group grK 1071 “Viruses of the Immune System” was held in Schlaifhausen from 23 to 24 may 2011. the meeting was organized by PhD students Jenny eckardt, tanja bräu, Silke tudor, and Sebastian bolduan and hosted 25 doc toral students from erlangen and six doctoral students from harvard, all members of the research training group, as well as 16 research group leaders from erlangen and six faculty members from harvard involved in the program. In addition, interested scientists from the participating research groups joined the retreat, which provided to the doctoral students an excellent opportunity to present their data to a selected audience and discuss their results in a relaxed atmosphere. this year, the organizers were happy to wel- come Prof. Dr. otto haller from freiburg as a guest speaker, who gave a talk on “host restriction factors: molecular in-sights into the antiviral functions of mx gtPases”. a further

highlight of the retreat was the award of the golden mic, presented to thomas Sommermann for his talk on “you’re either in or out – the nfκb pathway controls glucose trans-port in lymphocytes”. the Presentation award golden mic aims to honor “the most noteworthy presentation given by a student” at the retreat, who is elected by the audience. the participants agreed that the 2011 retreat was again a valuable platform for scientific exchange, practicing presen-tation skills, and getting together with PhD students and scientists from different research groups in an enjoyable scientific environment.

from 6 to 8 June 2011, the annual retreat of the network of three immunology research training groups of the Dfg (german research foundation) was held at Klosterhospiz neresheim and organized by the grK 520 (Würzburg). the network interconnects the Integrated research training group of the collaborative research centre Sfb 685 (Immuno -therapy, tübingen), the research training group grK 520 (Immunomodulation, Würzburg), and the erlangen research

rESEArCH TrAINING GrOUP 1660: NETwOrK MEETING 2011

Annual Joint retreat of the research Training Groups GrK 1660 (Erlangen), GrK 520 (würzburg) and the Inte grat ed research Training Group (IrTG) of the SFB 685 (Tübingen)

training group 1660 (adaptive Immunity). the annual re treat provides an excellent platform for doctoral students and proj-ect leaders to present their data and to discuss their research. It has been well established and become an integral part on the agenda of the network for over ten years. eight doctoral students of each research training group gave an oral presen-tation. all participants had the opportunity to present a poster on their results. this year, the fast track doctoral students from the erlangen grK 1660 – a pilot project for a doctoral fast track program from bachelor to PhD – were involved for the first time and impressively presented the results from their first-year lab rotations. likewise, the associated members and mD students of the grK 1660 successfully participated in the meeting. overall, the annual retreat was a great success and contributed once more to the scientific exchange within the network.

NEws ANd UpdAtEs

… ready for the welcome address Guest speaker Prof. Dr. Otto Haller

Participants of the Network Meeting 2011

Intrinsic Antiviral Immunity:

Nuclear Dot Proteins as a Cellular Defense against Herpesviruses

Thomas sTamminger · nina Tavalai insTiTuTe of CliniCal and moleCular virology

research of the last years has revealed that micro-bial infections are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors which give cells the capacity to resist pathogens. unlike the innate and adaptive part of the immune system, that require pathogen-induced signaling cascades in order to be switched on, these so-called intrinsic immune mechanisms are mediated by cellular proteins that are constitu-tively expressed and active before a pathogen enters the cell, thus serving as a front-line defense. Components of the intrinsic immunity have first been identified in the context of viral infections when it became apparent that cellular host factors like aPoBeC enzymes or the tripartite motif protein Trim5-alpha can confer resistance to retroviral infections and thus are able to affect viral tropism.

MICE LEttEr summer 2011 2

Scientific HigHligHtS Scientific HigHligHtS

3

autoimmune disease in general, but may also contribute in which tissue they manifest. under-standing the regulation of these genes while being exposed to different environmental factors may help us to understand the regulation of autoimmune genes in general and to define novel genetic targets for immune-intervention.

Mohammed JP, Fusakio ME, Rainbow DB, Moule C, Fraser HI, Clark J, Todd JA, Peterson LB, Savage PB, Wills-Karp M, Ridgway WM, Wicker LS, Mattner J.

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans- Induced Liver Autoimmunity. J Immunol. 2011; 187(1):337–4

Rainbow DB, Moule C, Fraser HI, Clark J, Howlett SK, Burren O, Christensen M, Moody V, Steward CA, Mohammed JP, Fusakio ME, Masteller EL, Finger EB, Houchins JP, Naf D, Koentgen F, Ridgway WM, Todd JA, Bluestone JA, Peterson LB, Mattner J, Wicker LS.

Evidence that Cd101 Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice. J Immunol. 2011; 187(1):325–36

Compartimentalization of Autoimmune responsesJoChen maTTner insTiTuTe of miCroBiology

C o n t I n u E d f r o M pA g E 1

Cd101 alleles regulate the resistance and susceptibility to liver disease induced by N. aro-infection. expression of the nod Cd101 allele induces a more tolerogenic milieu in the liver by promoting Treg responses whereas expression of the B6 Cd101 allele triggers an overzealouos T cell response upon infection with N. aro. The loss of Cd101 expression on dCs drives the enhanced ifn-γ and il-17 production by T cells and subsequently the induction of liver disease upon N. aro-infection.

our laboratory has investigated, whether a subnu-clear structure, termed nuclear domain 10 (nd10), contributes to the resistance of cells against her-pesvirus infections. nd10, alternatively termed Pml nuclear bodies, are dot-like structures of the cell nucleus, that are defined by the distinct accumula-tion of specific cellular proteins like Pml, hdaxx and sp100. approximately 15 years ago, it was detected that herpesviral dna associates with these protein accumulations within the nucleus, however, the functional significance of this juxtapo-sition was not clear. By establishing primary human fibroblasts with an rna-interference mediated depletion of the major nd10 proteins Pml, sp100 or hdaxx we could show, that these proteins act as cellular restriction factors by inducing a silencing of viral gene expression. moreover, our research revealed that specific viral proteins are able to an-tagonize this cellular silencing mechanism. This establishes a delicate balance between cellular defense and viral antagonism which determines whether the herpesvirus enters the productive re p-lication cycle or the latency program.

Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T. Evidence for a dual antiviral role of the major ND10 component Sp100 during the immediate-early and late phase of the human cytomegalovirus replication cycle. J. Virol. 2011, Jul 2 [Ebup ahead of print]

Adler M, Tavalai N, Müller R, Stamminger T. Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100. J. Gen.Virol. 2011; 92:1532–8.

Tavalai N, Stamminger T. Instrinsic cellular defense mechanisms targeting cytomegalovirus.Virus Res. 2011; 157:128–33.

Antagonization of nuclear domain 10 (ND10)-mediated repression by cytomegalovirus (HCMV) infection. subpanels a-d: intact nd10 (as detected by indirect immunofluorescence analysis using a monoclonal antibody against the Pml protein) in non-infected primary human fibroblasts; nd10 are defined as accumulations of specific cellular proteins like Pml, sp100 and hdaxx. subpanels e-h: nd10 are disrupted by infection of fibroblasts with cytomegalovirus (hCmv). daPi: detection of the nucleus. intact nd10 are able to induce a silencing of viral genomes. This cellular repression mechanism is antagonized by specific viral proteins, leading to productive viral replication.

Microbial infec-tions are not only controlled by innate and adaptive immune mechanisms but also by cellular restriction factors

PML, Sp100 and hDaxx … act as cellular restriction factors by inducing a silencing of viral gene expression

A delicate balance between cellular defense and viral antagonism

Allelic variations alter the suscepti-

bility of individuals not only to auto-immune disease

in general, but may also contribute

in which tissue they manifest

MICE LEttEr summer 2011 4

ReseARCH TRAiNiNg gRoup 1071: ANNuAl ReTReAT 2011

10th Retreat of the Research Training group gRK 1071 in schlaifhausen with participation of the Harvard phD students and Faculty Members

The 10th retreat of the dfg (german research foundation) research Training group grK 1071 “viruses of the immune system” was held in schlaifhausen from 23 to 24 may 2011. The meeting was organized by Phd students Jenny eckardt, Tanja Bräu, silke Tudor, and sebastian Bolduan and hosted 25 doc toral students from erlangen and six doctoral students from harvard, all members of the research Training group, as well as 16 research group leaders from erlangen and six faculty members from harvard involved in the program. in addition, interested scientists from the participating research groups joined the retreat, which provided to the doctoral students an excellent opportunity to present their data to a selected audience and discuss their results in a relaxed atmosphere. This year, the organizers were happy to wel- come Prof. dr. otto haller from freiburg as a guest speaker, who gave a talk on “host restriction factors: molecular in-sights into the antiviral functions of mx gTPases”. a further

highlight of the retreat was the award of the golden mic, presented to Thomas sommermann for his talk on “you’re either in or out – The nfκB pathway controls glucose trans-port in lymphocytes”. The Presentation award golden mic aims to honor “the most noteworthy presentation given by a student” at the retreat, who is elected by the audience. The participants agreed that the 2011 retreat was again a valuable platform for scientific exchange, practicing presen-tation skills, and getting together with Phd students and scientists from different research groups in an enjoyable scientific environment.

from 6 to 8 June 2011, the annual retreat of the network of three immunology research training groups of the dfg (german research foundation) was held at Klosterhospiz neresheim and organized by the grK 520 (Würzburg). The network interconnects the integrated research Training group of the Collaborative research Centre sfB 685 (immuno -therapy, Tübingen), the research Training group grK 520 (immunomodulation, Würzburg), and the erlangen research

ReseARCH TRAiNiNg gRoup 1660: NeTwoRK MeeTiNg 2011

Annual Joint Retreat of the Research Training groups gRK 1660 (erlangen), gRK 520 (würzburg) and the inte grat ed Research Training group (iRTg) of the sFB 685 (Tübingen)

Training group 1660 (adaptive immunity). The annual re treat provides an excellent platform for doctoral students and proj-ect leaders to present their data and to discuss their research. it has been well established and become an integral part on the agenda of the network for over ten years. eight doctoral students of each research training group gave an oral presen-tation. all participants had the opportunity to present a poster on their results. This year, the fast track doctoral students from the erlangen grK 1660 – a pilot project for a doctoral fast track program from Bachelor to Phd – were involved for the first time and impressively presented the results from their first-year lab rotations. likewise, the associated members and md students of the grK 1660 successfully participated in the meeting. overall, the annual retreat was a great success and contributed once more to the scientific exchange within the network.

nEws And updAtEs

… ready for the welcome address Guest speaker Prof. Dr. Otto Haller

Participants of the Network Meeting 2011

MICE LEttEr Summer 2011

MICE LetterSummer 2011

C O N t E N t

Scientific Highlights p. 1– 3•Compartimentalization of Autoimmune Responses

• Intrinsic Antiviral Immunity

News and Updates p. 4 – 5•Research Training Group 1660: Network Meeting 2011

•Research Training Group 1071: Annual Retreat 2011

•m4 Award

Upcoming Events p. 6 •MICE Immunological Colloquium – Preview Winter 2011/2012

•Conferences (Co-)Organized by MICE Members

•Further Conferences of Interest

5 MICE LEttEr Summer 2011 6 Summer 2011

Factors leading to the development

of immune responses against specific antigens

in an organ-specific manner remain

largely unknown

The suppression of CD101 expression

promotes the severe liver autoimmunity in NOD.B6 Cd101

mice

Triplebodies which... efficiently mediate

killing of AML stem cells by NK cells

Compartimentalization of Autoimmune responses

Infection Converts Protec tive Alleles for Type 1 Diabetes into Susceptibility Alleles for Primary Biliary Cirrhosis

Jochen mattner InStItute of mIcrobIology

autoimmune diseases are driven by complex interactions of environmental factors with genetic traits. although autoimmune genes often cluster together in defined patient populations that are prone to the development of autoimmune disease, the factors leading to the development of immune responses against specific antigens in an organ-specific manner remain largely unknown. utililizing noD congenic mice as model, we describe that introgression of the Cd101 allele encoding the negative costimulatory molecule cD101 from b6 mice onto the noD background protects mice from the development of spontaneous type 1 diabetes (t1D); when infected, however, with an ubiquitous alphaproteo -bacterium, noD mice carrying the b6 Cd101 allele (noD.b6 Cd101) are prone to develop severe liver autoimmunity resembling primary biliary cirrhosis (Pbc) in humans. In contrast to the enhanced expression of cD101 on regulatory t cells in naïve noD.b6 Cd101 mice that may contribute to the protection from t1D, infection triggers a downregulation of cD101 on Dcs and granulocytes correlating with more severe liver disease in noD.b6 Cd101 mice compared to noD mice. While the suppression of cD101 expression on Dcs promotes a hyperreactive t cell response, downregulation of cD101 on granulocytes affects their recruitment to the liver prolonging bacterial persistence. Infection of cD101 knockout mice results in more severe liver disease compared to wild-type mice sug-gesting that the suppression of cD101 expres-sion promotes the severe liver autoimmunity in noD.b6 Cd101 mice. thus, allelic variations alter the susceptibility of individuals not only to

Scientific HigHligHtS

NEws ANd UpdAtEs

Prof. Dr. georg fey, Division of genetics, Depart- ment of biology from the university of erlangen- nuremberg, has been awarded the m4 award of the bavarian ministry of economic affairs, Infrastructure, transport and technology, and the federal ministry of education and research together with his cooperation partners Prof. Dr. Karl-Peter hopfner (gene center of the uni-versity of munich – lmu) and PD Dr. Dr. fuat oduncu (university hospital of the university of munich - lmu). they have developed triple-bodies which recognize two antigens on acute myeloid leukemia (aml) stem cells and cD16 on natural Killer (nK) cells and thereby effi-

ciently mediate killing of aml stem cells by nK cells. their project will be funded with € 500,000 over the next two years and has high relevance for the personalized treatment of acute myeloid leukemia. the researchers have founded the company Spectramab, a spin-off from the univer-sity of erlangen-nuremberg located in martinsried near munich, with the objective to bring the triple-bodies with the ability to eliminate cancer stem cells to clinical application. the m4 award aims at supporting research projects committed to the development of new therapeutic approaches and techniques in the field of personalized medi-cine with a high economic potential.

A successful team: PD Dr. Dr. Oduncu, Prof. Dr. Fey (CSO SpectraMab), Prof. Dr. Jacob (CEO SpectraMab), and Prof. Dr. Hopfner ( from left to right )

m4 AwArD

research Team from the University of Erlangen-Nuremberg and the Ludwig-Maximilians-University Munich recieves Grant for Leukemia research 18.10. 2011

To be announced

25.10. 2011

Andreas Diefenbach freiburg

Development and Function

of Innate Lymphocytes

08.11.2011

Francesca Granucci milan, Italy

The Multifaceted Roles

of CD14 in Innate Immunity

15.11.2011

Eicke Latz bonn

Mechanisms of Inflam-

masome Activation in

Inflammatory Diseases

22.11. 2011

Manolis Pasparakis cologne

Epithelial Regulation

of Intestinal Inflammation

and Cancer

29.11. 2011

Christopher D. Gregory edinburgh, uK

The Role of Apoptosis

in Conditioning the Micro-

environment of Tumours

06.12.2011

Michael Sixt Klosterneuburg, austria

Mechanisms of Leukocyte

Chemotaxis

Special Lecture on Monday12.12. 2011

Kenneth Murphy St. louis, uSa

Title to be announced

20.12. 2011

To be announced

10.01.2012

To be announced

17.01. 2012

Ofer Mandelboim Jerusalem, Israel

Proteins and miRNA-

mediated Regulation

of NK Cell Activity

24.01. 2012

robert M. Strietercharlottesville, uSa

The Role of CXC Chemo-

kines in Lung Cancer

31.01. 2012

Tariq Enver london, uK

Title to be announced

07.02. 2012

To be announced

UpCOMINg EvENts

MICE Immunological Colloquium – Preview winter 2011/2012

Conferences (Co-)organized by MICE members

October 2 – 4, 2011

1st International SFB 796 Conference: Mechanisms of viral host cell manipulation: From plants to humansbamberg

www.sfb796.de

October 9– 14, 2011

3rd Autumn School

“Current Concepts

in Immunology” of

the German Society

of Immunology bad Schandau

www.herbstschule.de

Further Conferences of Interest

October 3 – 4, 2011

5th International

Vilnius Course

“Update on Paediatric

Infectious Diseases”Vilnius, lithuaniawww.vilniuscourse.com

March 18 – 21, 2012

world Immune

regulation

Meeting-VIDavos, Switzerlandwww.wirm.ch

Publishermedical Immunology campus erlangen

Schlossgarten 4 | 91054 erlangen

Phone +49.9131.85.2 67 84 Fax +49.9131.85.2 21 01

www.mice.uni-erlangen.de

Conceptual Design and EditorDr. annette grohmann V.i.S.d.P.

Subscription via Email to:aegrohma@viro.med.uni-erlangen.de

Please note that the authors are responsible for the content of their contributions.

We are looking forward to suggestions for the next mIce letter.

Please send material to:aegrohma@viro.med.uni-erlangen.de

MICE LEttEr Summer 2011

MICE LetterSummer 2011

C O N t E N t

Scientific Highlights p. 1– 3•Compartimentalization of Autoimmune Responses

• Intrinsic Antiviral Immunity

News and Updates p. 4 – 5•Research Training Group 1660: Network Meeting 2011

•Research Training Group 1071: Annual Retreat 2011

•m4 Award

Upcoming Events p. 6 •MICE Immunological Colloquium – Preview Winter 2011/2012

•Conferences (Co-)Organized by MICE Members

•Further Conferences of Interest

5 MICE LEttEr Summer 2011 6 Summer 2011

Factors leading to the development

of immune responses against specific antigens

in an organ-specific manner remain

largely unknown

The suppression of CD101 expression

promotes the severe liver autoimmunity in NOD.B6 Cd101

mice

Triplebodies which... efficiently mediate

killing of AML stem cells by NK cells

Compartimentalization of Autoimmune responses

Infection Converts Protec tive Alleles for Type 1 Diabetes into Susceptibility Alleles for Primary Biliary Cirrhosis

Jochen mattner InStItute of mIcrobIology

autoimmune diseases are driven by complex interactions of environmental factors with genetic traits. although autoimmune genes often cluster together in defined patient populations that are prone to the development of autoimmune disease, the factors leading to the development of immune responses against specific antigens in an organ-specific manner remain largely unknown. utililizing noD congenic mice as model, we describe that introgression of the Cd101 allele encoding the negative costimulatory molecule cD101 from b6 mice onto the noD background protects mice from the development of spontaneous type 1 diabetes (t1D); when infected, however, with an ubiquitous alphaproteo -bacterium, noD mice carrying the b6 Cd101 allele (noD.b6 Cd101) are prone to develop severe liver autoimmunity resembling primary biliary cirrhosis (Pbc) in humans. In contrast to the enhanced expression of cD101 on regulatory t cells in naïve noD.b6 Cd101 mice that may contribute to the protection from t1D, infection triggers a downregulation of cD101 on Dcs and granulocytes correlating with more severe liver disease in noD.b6 Cd101 mice compared to noD mice. While the suppression of cD101 expression on Dcs promotes a hyperreactive t cell response, downregulation of cD101 on granulocytes affects their recruitment to the liver prolonging bacterial persistence. Infection of cD101 knockout mice results in more severe liver disease compared to wild-type mice sug-gesting that the suppression of cD101 expres-sion promotes the severe liver autoimmunity in noD.b6 Cd101 mice. thus, allelic variations alter the susceptibility of individuals not only to

Scientific HigHligHtS

NEws ANd UpdAtEs

Prof. Dr. georg fey, Division of genetics, Depart- ment of biology from the university of erlangen- nuremberg, has been awarded the m4 award of the bavarian ministry of economic affairs, Infrastructure, transport and technology, and the federal ministry of education and research together with his cooperation partners Prof. Dr. Karl-Peter hopfner (gene center of the uni-versity of munich – lmu) and PD Dr. Dr. fuat oduncu (university hospital of the university of munich - lmu). they have developed triple-bodies which recognize two antigens on acute myeloid leukemia (aml) stem cells and cD16 on natural Killer (nK) cells and thereby effi-

ciently mediate killing of aml stem cells by nK cells. their project will be funded with € 500,000 over the next two years and has high relevance for the personalized treatment of acute myeloid leukemia. the researchers have founded the company Spectramab, a spin-off from the univer-sity of erlangen-nuremberg located in martinsried near munich, with the objective to bring the triple-bodies with the ability to eliminate cancer stem cells to clinical application. the m4 award aims at supporting research projects committed to the development of new therapeutic approaches and techniques in the field of personalized medi-cine with a high economic potential.

A successful team: PD Dr. Dr. Oduncu, Prof. Dr. Fey (CSO SpectraMab), Prof. Dr. Jacob (CEO SpectraMab), and Prof. Dr. Hopfner ( from left to right )

m4 AwArD

research Team from the University of Erlangen-Nuremberg and the Ludwig-Maximilians-University Munich recieves Grant for Leukemia research 18.10. 2011

To be announced

25.10. 2011

Andreas Diefenbach freiburg

Development and Function

of Innate Lymphocytes

08.11.2011

Francesca Granucci milan, Italy

The Multifaceted Roles

of CD14 in Innate Immunity

15.11.2011

Eicke Latz bonn

Mechanisms of Inflam-

masome Activation in

Inflammatory Diseases

22.11. 2011

Manolis Pasparakis cologne

Epithelial Regulation

of Intestinal Inflammation

and Cancer

29.11. 2011

Christopher D. Gregory edinburgh, uK

The Role of Apoptosis

in Conditioning the Micro-

environment of Tumours

06.12.2011

Michael Sixt Klosterneuburg, austria

Mechanisms of Leukocyte

Chemotaxis

Special Lecture on Monday12.12. 2011

Kenneth Murphy St. louis, uSa

Title to be announced

20.12. 2011

To be announced

10.01.2012

To be announced

17.01. 2012

Ofer Mandelboim Jerusalem, Israel

Proteins and miRNA-

mediated Regulation

of NK Cell Activity

24.01. 2012

robert M. Strietercharlottesville, uSa

The Role of CXC Chemo-

kines in Lung Cancer

31.01. 2012

Tariq Enver london, uK

Title to be announced

07.02. 2012

To be announced

UpCOMINg EvENts

MICE Immunological Colloquium – Preview winter 2011/2012

Conferences (Co-)organized by MICE members

October 2 – 4, 2011

1st International SFB 796 Conference: Mechanisms of viral host cell manipulation: From plants to humansbamberg

www.sfb796.de

October 9– 14, 2011

3rd Autumn School

“Current Concepts

in Immunology” of

the German Society

of Immunology bad Schandau

www.herbstschule.de

Further Conferences of Interest

October 3 – 4, 2011

5th International

Vilnius Course

“Update on Paediatric

Infectious Diseases”Vilnius, lithuaniawww.vilniuscourse.com

March 18 – 21, 2012

world Immune

regulation

Meeting-VIDavos, Switzerlandwww.wirm.ch

Publishermedical Immunology campus erlangen

Schlossgarten 4 | 91054 erlangen

Phone +49.9131.85.2 67 84 Fax +49.9131.85.2 21 01

www.mice.uni-erlangen.de

Conceptual Design and EditorDr. annette grohmann V.i.S.d.P.

Subscription via Email to:aegrohma@viro.med.uni-erlangen.de

Please note that the authors are responsible for the content of their contributions.

We are looking forward to suggestions for the next mIce letter.

Please send material to:aegrohma@viro.med.uni-erlangen.de