Interferon-gamma and immune system
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Transcript of Interferon-gamma and immune system
By Wat Mitthamsiri, MD.
Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
Interferon-Gamma
And
Immune System
Outline
• Introduction • What is interferon (IFN) • Classification of IFN • Interferon gamma (IFN-γ)
– History and biology – Roles with other immune components – Roles in infection defense – Roles in autoimmunity – Roles in allergy and hypersensitivity
INTRODUCTION
What is interferon (IFN)
• Interferons are proteins which produce antiviral and antiproliferative responses in cells.
• On the basis of their sequence interferons are classified into five groups: α, α-II (or omega), β, delta (or trophoblast) and γ.
• Except for γ-interferon, the sequence of all the others are related
PROSITE documentation PDOC00225, Swiss Institute of Bioinformatics, http://prosite.expasy.org/cgi-bin/prosite/prosite-search-ac?PDOC00225#ref1
InterPro: protein sequence analysis & classification, EMBL-EBI, http://www.ebi.ac.uk/interpro/entry/IPR000471
What is interferon (IFN)
• Roles of IFN: – Decrease tumor growth, inflammation, and
angiogenesis – Innate immunity (IFN-α and IFN-β) – Adaptive immunity (IFN-γ)
O Meyer, Joint Bone Spine 76 (2009) 464–473
Classification of IFN
• 3 main classes:
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
Classification of IFN
• Type I IFNs – Encoded by 17 nonallelic genes
• Lack introns • Located on chromosome 9 in humans
– Glycosylated proteins,160-200 amino acids – Sharing 30% to 55% homology
• Type II IFN – 140 amino acids and shares no homology
with type I IFNs
O Meyer, Joint Bone Spine 76 (2009) 464–473
Classification of IFN
• Type III IFNs: 3 IFN molecules – IL-28A, IL-28B, and IL-29 – Co-produced with IFN-β – But act by binding to a different receptor from
type I IFN receptors
O Meyer, Joint Bone Spine 76 (2009) 464–473
O Meyer, Joint Bone Spine 76 (2009) 464–473
INTERFERON-GAMMA History and biology
Interferon-gamma (IFN-γ)
• Sole type II IFN • Made primarily by T cells and NK cells • More of an interleukin than an interferon?
– Modest antiviral activity – Prominent derivation from T lymphocytes – Wide-ranging functions
• Play roles in cellular and allergic immunity
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ: General history
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1965 Induction of an IFN activity in human PBMC by phytohemagglutinin
1966 Ag-specific induction of IFN activity during virus infections
1972 New IFN was named ‘immune IFN’
1973 IFN produced during DTH reactions named ‘Type II IFN’
1980 Nomenclature Committee: definitive name ‘IFN-γ’
1982 Dimeric structure of IFN- γ suggested, Cloning of IFN- γ from cDNA
IFN-γ: Structure
• Dimeric in solution • Each subunit
– 6 α-helices, that comprise 62% of the structure
– No β-sheet – Composed of 140 amino
acids – No homology with type I
IFNs S E. Ealick, et al., Science, New Series, Vol. 252, No. 5006 (May 3, 1991), pp. 698-702
O Meyer, Joint Bone Spine 76 (2009) 464–473
IFN-γ: Sources
• During innate immune responses – Natural killer (NK) cells – Natural killer T (NKT) cells – Macrophages – Dendritic cells
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Sources
• In adaptive immunity – CD8+ T cells – Control of infection, – CD4+ T helper 1 (Th1) subset
• Promotes inflammatory responses • Clearance of intracellular pathogens • Class-switching to IgG2a, IgG2b, and IgG3
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Gene • Human chromosome 12 • Cytogenetic Location: 12q14 • Molecular Location on chromosome 12:
– Base pairs 68,154,769 to 68,159,740
National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2013 Sep 16 [cited 2014 April 3]. Available from: http://ghr.nlm.nih.gov/gene/IFNG.
IFN-γ: Expression regulation
• In innate immunity – IFN-γ production response to constitutive
expression of transcription factors • Eomes and T-bet (NK cells) • T-bet (NKT)
– These transcription factors bind to regulatory elements that are already accessible within the Ifng locus, leading to activation of Ifng transcription
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Expression regulation
• In adaptive immunity – Expression by CD4+and CD8+ T cells – Differentiation process of naïve CD4+ or
CD8+ T cells to Th1 or cytotoxic T effector cells requires:
• T cell receptor (TCR) stimulation • Multiple rounds of cell division • Induction of T-bet • Epigenetic modifications within the Ifng gene
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Expression regulation
• Epigenetic regulation: long non-coding RNAs (lncRNAs) Tmevpg1 (also known as NeST) – Positively contribute to IFN-γ production by
CD4+ and CD8+ T cells – Tmevpg1 is adjacent to the Ifng gene – Encoded on the DNA strand opposite to that
coding IFN-γ
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Expression regulation
• Epigenetic regulation: long non-coding RNAs (lncRNAs) Tmevpg1 (also known as NeST) – Tmevpg1 transcription is dependent upon
transcription factors, Stat4 and T-bet • Which also influence Ifng transcription in CD4+
Th1 T cells – Tmevpg1 transgenic mice:
• Increased IFN-γ • Immune to salmonella infection
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• IFN-γ enhances TLR-
induced TNF production by disrupting an IL-10-mediated inhibitory loop
• Increased activity of GSK3
• Negatively regulates IL-10 expression by suppressing activation of transcription factors CREB and AP-1
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• IFN-γ enhances TLR-induced
IL-6 and IL-12 production
• Disrupts inhibitory loop mediated by Notch target genes Hes1 and Hey1
• Downregulates intracellular NICD2 amounts
• Inhibits expression of Hes1 and Hey1
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• Via regulation of IL-1R and TLR signaling
• Inhibits IL-1 signaling in macrophages by downregulating IL-1RI expression
• Blocks induction of MMP downstream of TLR signaling by
• Superinduce transcription repressor ATF3 • Inhibit transcription activators CREB and
AP-1 • Inhibits CREB activity by suppressing its serine
phosphorylation • Inhibits AP-1 by downregulating nuclear protein
levels of its subunits
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• Inhibits osteoclastogenesis and
bone resorption
• Suppress expression and signal transduction of RANK, CSF-1R, and TREM2
• (Receptors critical for the process of osteoclastogenesis)
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• Attenuates fibrosis by:
• Suppresses TGF-βR signaling by
• Induction of inhibitory SMAD (SMAD7) • Direct inhibition of SMAD3 by STAT1
• Inhibits IL-4R signaling by induction of SOCS1
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• In Th1 cell differentiation
• IFN-γ-STAT1 signaling is critical for induction of T-bet and thus for sustaining the positive feedback loop
• Leads to heightened production of IFN-γ.
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• IFN-γ blocks Th2 cell differentiation
• By inhibiting IL-4-STAT6 signaling
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• IFN-γ and STAT1 can block Th17 cell differentiation
• Mechanism of action is not clear • Possibly suppresses Th17 cell by targeting
STAT3 (shown by dotted lines)
• Inhibit aryl hydrocarbon nuclear receptor (AHR)
• Suppression of TGF-β and IL-1 signaling by IFN-γ may contributes to inhibition of Th17 cell differentiation (not depicted)
IFN-γ: Signalling pathways
X Hu, et al., Immunity 31, October 16, 2009, 539-550.
• Regulates Treg cell differentiation and function.
• Block TGFβ-mediated Treg cell differentiation
• Upregulates expression of T-bet in Foxp3+ Treg cells
• Promotes expression of CXCR3 that regulates homing of T-bet+ FoxP3+ Treg cells to sites of Th1 cell inflammation
INTERFERON-GAMMA Roles with other immune components
IFN-γ and macrophages
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1969 Lymphocyte-mediated activation of macrophagesMIF responsible?
1979 Several macrophage-activating factor (MAF) assays established
1983 Anti-IFN-γ antibody neutralizes MAF preparations
1985 Cloned IFN-γ possesses MAF activity
IFN-γ and macrophages
• Driving differentiation from inactive monocytes into potent effector M1 activated macrophages – Enhanced adherence, phagocytosis,
degranulation, and production of reactive oxygen and nitrogen molecules
• Responsible for their accumulation at the site of CMIR as cells newly capable of killing intracellular pathogens and cancers
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and macrophages
• Activated M1 macrophages – Induced by IFN-γ – High producers of IL-1β, TNF-α, IL-6, IL-12,
and IL-23 – but not IL-10
– =>Proinflammatory and participate in Th1
polarization
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and NK cells
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1980 IFN-γ upregulates NK activity
1983 IL-2 may induce IFN-γ in NK cells
1993 Novel IFN-γ-coinducing factor IGIF/IL-18
1995 IL-18 induces IFN-γ in NK cells
1991 IL-12 induces IFN-γ in NK cells
IFN-γ and NK cells+PMN
• Stimulates killing by NK cells and neutrophils
• Stimulates adherence of leukocytes to endothelial cells through induction of ICAM-1
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and APCs + DCs
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1982 IFN-γ enhances MHC Class II expression in mononuclear phagocytes
1984 IFN-γ induces enzymatic breakdown of tryptophan
2000 IFN-γ optimizes IL-12 production by DCs IFN-γ-induced IDO conditions DCs to
become tolerogenic
1990 IFN-γ induces IDO in vivo
1996 IFN -γ enhances MHC Class II expression in DCs
IFN-γ and APCs + DCs
• Directly stimulates Ag processing
• Stimulates antigen presentation via increased MHC class I and II expression
• Stimulates cytokine production
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and Treg cells
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1995 CD4+CD25+ Treg cells defined
2005 Defective functioning of Treg cells in IFN -γR KO mice with collagen-induced arthritis (CIA)
2006 IFN-γ can convert CD4+CD25 cells into CD4+ Treg cells able to suppress experimental autoimmune encephalomyelitis (EAE)
Release of IFN-γ by Treg cells
IFN-γ and T-helper cells
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
1973 T cell-replacing factor (TRF, T cell help for B cells) described
1977 Type II IFN inhibits antibody production in vitro
2005 Th17 cell lineage defined in mice IFN-γ inhibits differentiation of Th17 cells
and IL-17 production by activated Th memory cells
1984 IFN-γ proposed as a TRF
1988 Th1 and Th2 clones described Role of IFN-g in Th1/Th2 paradigm
INTERFERON-GAMMA Roles in infection defense
IFN-γ and infection defense
• Most important in vivo role • Establishing effective response towards
pathogens whose elimination from the body depends on phagocytosis and intracellular killing
• Weakly inhibits viral replication
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and infection defense
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
Pathogen entry
NK cells produce IFN-γ primes mononuclear phagocytes for production of monokines:
TNF-a and IL-12
IFN-γ & TNF-a augment bacteriostatic potential of phagocytes
Guided by IL-12, Th1 response is mounted
Additional IFN-γ production by activated CD4+ and CD8+ T cells
IFN-γ and infection defense
• In Listeria infection, IFN-γ can: – Augment normal resistance – Restore compromised resistance – Rx with neutralizing Ab to IFN-γ abrogated
resistance – IFN-γ production during the first 2 days of
infection was critical for development of protective Ag-specific T cells
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and infection defense
• In Mycobacterial infections – Application of IFN-γ on skin lesions of
lepromatous leprosy patients caused increased infiltration with lymphocytes and reduction in the local bacterial load
– Mice with a disrupted gene for the IFN-γ receptor were found to fail controlling infection with M. bovis.
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and infection defense
• Mycobacterial infections in IFN-γ deficient mice – Unable to control sublethal doses M.
tuberculosis or M. bovis – Bacteria multiplied more extensively and
caused more widespread damage in affected tissues.
– Compromised in both innate resistance in early phase of infection, and also later development of protective immunity
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and infection defence
• Important factor in directing the immune response towards the Th1 pathway
• Mitigates excessive extramedullary myelopoiesis
• Responsible for apoptosis of CD4+ T cells in the later phases of the immune response to mycobacteria
• Responsible for the appearance of ‘immunosuppressive’ macrophages
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
INTERFERON-GAMMA Roles in autoimmunity
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ and autoimmunity
• Mechanism is remain unclear • Epidermal transgenic expression of IFN-γ
leads to – Anti-dsDNA, – Anti-histone autoAb – Glomerulonephritis
• Transgenic IFN-γ expression in other sites does not lead to systemic autoimmunity??
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ and autoimmunity
• Possibly supporting evidence – Ability of IFN-γ to
• Promote B cell IgG class switching to more pathogenic autoAb
• Activation of IgG Fc receptors and complement • Contributes to disease severity
– In end organ damage, infiltration of IFN-γ secreting T cells resulting in macrophage activation, inflammation, and tissue damage
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ and autoimmunity
• Possibly supporting evidence – Mutated mice with reduced decay of IFN-γ
mRNA • Increased IFN-γ signaling and accumulation of
follicular helper T (Tfh) cells • Increased germinal center B cells and autoAb • IFN -γR-deficiency in these mice can prevent the
development of lupus
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ and autoimmunity
• Possibly contradict evidence – The experimental autoimmune diseases,
EAE, EAU and CIA, = Th17-driven – Conditions for optimal in vitro induction of
naive T cells differentiation into Th17 cells by IL-23 were found to include neutralization of endogenous IFN-γ
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and autoimmunity
• Possibly contradict evidence – Ablation of IFN-γ resulted in increased
numbers of IL-17-producing T cells – Conclusion: Endogenous IFN-γ inhibits
differentiation of Th17 cells – Ablation of endogenous IFN-g should boost
disease in EAE and CIA.
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and autoimmunity
• Possibly contradict evidence – Blocking of autoimmune diseases can be
done by injection of syngeneic Treg cells – In vitro treatment of CD4+CD25 cells with
IFN-γ cause their conversion into CD4+ Treg cells
– Evidence exists for induced Treg cells to rapidly release IFN-γ, that may be important for their suppressive activity
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
IFN-γ and autoimmunity
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ as a therapeutic target?
• Fontolizumab, – Humanized monoclonal Ab against IFN-γ – Showed some efficacy in patients with
Crohn’s disease – Phase II clinical trial investigating its use in
rheumatoid arthritis was terminated because the first phase did not meet the endpoint
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ as a therapeutic target?
• Amgen’s AMG 811 – Human monoclonal Ab – Being evaluated in safety trials with subjects
with DLE and subjects with SLE with and without glomerulonephritis
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
IFN-γ as a therapeutic target?
• Non-specific targeting of IFN-γ – Impact both innate and adaptive immunity – Deficiency of IFN-γ is associated with severe
infection • Targeting to cellular components
regulating IFN-γ expression, such as lncRNA Tmevpg1, may provide greater therapeutic benefit without adverse effect on responses to infection
K M Pollard, et al., Discov Med, 2013, 16(87):123-131.
INTERFERON-GAMMA Roles in allergy and hypersensitivity
IFN-γ and allergy
• Allergic inflammatory tissue has prominent presence of IFN-γ
• IFN-γ exacerbates allergic inflammation through its ability to – Activate accessory cell function – Stimulate cytokine secretion – Induce adhesion molecule expression – Activate eosinophils and neutrophils
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and allergy
• IFN-γ promotes allergic inflammation – IFN-γ–producing Th1 lymphocytes exacerbate
murine asthma – Th1-like processes are particularly prevalent
in patients with severe asthma, especially those with irreversible obstruction and neutrophilic inflammation
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and allergy
• It is frequently stated that the immune response to allergens in non-allergic subjects is characterized by Th1-like lymphocyte responses
• …But without CMIR and cellular inflammation
J W Steinke, et al., Middleton’s Allergy 8th edition, 2013, 65-82.
IFN-γ and DTH
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
• Exogenous IFN-γ was found to reverse inhibition of the DTH response by anti-CD4 or anti-IL-2R Ab in mouse model • supporting the concept that production of
IFN-γ by TH1 cells is essential for the reaction • There was report of IFN-γ potentiates
contact sensitivity
IFN-γ and DTH
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
• There were ambiguity in reports analyzing the role of IFN-γ in DTH reactions • This reflects the pathogenic complexity of the
systems under study • Effects may differ depending on • Ag used (protein or hapten) • Route of exposure (injection or contact with
the skin) • Time point during the reaction (during the
sensitization or the elicitation phase)
IFN-γ and DTH
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
• DTH reactions rely on both natural and acquired immune response mechanisms
• IFN-γ may act differently on these components
IFN-γ and Shwartzman reaction
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
• 2 varients: • Localized • Generalized
• Both are two-stage phenomena • Preparative (sensitizing) injection of
endotoxin • Eliciting (provoking) injection followed after
about 24 h
IFN-γ and Shwartzman reaction
A. Billiau, P. Matthys Cytokine & Growth Factor Reviews 20 (2009) 97–113
• Example of human model: • Thrombohemorrhagic shock that sometimes
occurs in humans with meningococcal sepsis • In mouse model with Pre-treatment with
neutralizing anti-IFN-γ • Completely protected against this reaction • Reduced production of circulating TNF
following the eliciting dose
TAKE HOME MESSAGE
Take home message
• IFN-γ is the only type II IFN • It’s a cytokine that is critical for innate and
adaptive immunity • Its action mainly via JAK-STAT pathway • It has multifaceted roles: Infection defense
(esp. intracellular pathogens) , CMIR, autoimmunity, allergy and hypersensitivity