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![Page 1: Immune Effectors Kathleen Kelly kkelly@mednet.ucla.edu 6-5562 Reading Immunobiology (5 th Edition) Janeway, Travers, Walpert and Capra Chapter 10 (p. 381-402)](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649ee75503460f94bf7c41/html5/thumbnails/1.jpg)
Immune EffectorsKathleen Kelly [email protected]
ReadingImmunobiology (5th Edition) Janeway, Travers, Walpert and Capra
Chapter 10 (p. 381-402) and Chapter 8 (p. 295-340)
Agnello D, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 23:147-161, 2003.
Mak, TM & Lohoff. Roles of Interferon Regulatory Factors in T-helper-cell Differentiation. Nature Reviews Immunol. 5:125-135, 2005.
Russell, JH & Ley, TJ. Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol. 323-370, 2002.
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Formation of Effector T Cells
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T Effector Cells T cell subsets are the armed assassins of the
adaptive immune response CD8
Cytotoxic T cells (CTL) Effector function is to lyse target cells (infected,
tumor) CTL - effector molecules are lytic granules
perforin/granzyme pathway CD4
T helper cells Effector function is to produce certain cytokines Th1 - effector cytokine is IFN
• - Activate MQ & FasL/FADD mediated cytotoxicity Th2 - effector cytokine is IL-4
• - help B cells/Ab production
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Different Classes of PathogensElicit Different T Effector Subsets
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Effector Function of CTLEffector function is to
lyse target cells Virus infected Tumor
MHC Class I restrictedContact-dependentPerforin/Granzyme
mediated cytotoxicity Lytic granules are
produced & released from CD8+ CTL
Granules induce apoptosis
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Pathways of Apoptosis
Russell, JHAnn. Rev. Immunol.20:323, 2002
Cytotoxicgranules
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Granzyme B but not FADD (FasL) Pathway is Necessary for MHC Class I Restricted Responses (GvH)
Granzyme B-/-
FasL-/-
WildType
FasL & Granzyme B-/-
Syngeneic
Graubert, TA et al. J Clin Invest. 100:904, 1997
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FADD (FasL) but not Perforin/Granzyme B Pathway is Necessary for
MHC Class II Restricted Response
Granzyme B-/-
FasL-/-
FasL & Granzyme B-/-
Syngeneic
Perforin-/-
Graubert, TA et al. J Clin Invest. 100:904, 1997
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CTL Lytic GranulesLytic granules:
Are synthesized de novo after initial T cell activation (1-3 days) (NK cell killing is immediate)
After activation CTL can kill multiple cells, ie multiple times.
Requires post-translational modification Perforin (action is Ca++ dependent)
Similar in structure to C9, which polymerizes to form membrane pores on target cell surface by binding to perforin receptors that are induced by IFN
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Granule Exocytosis Pathway
Effector molecules are preformed in granules and undergo granule exocytosis pathway PI-3 kinase
RAC-1
PAC-1
MAPK kinase
ERK Russell, JH, Ann. Rev. Immunol.20:323, 2002
cation-dependentMannose-P-6 R
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CTL Lytic GranulesLytic granules:
Granzymes Serine proteases
• Granzyme B cleaves caspase 3
Other enzymes with undefined function Granulysin Orphan granzymes
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Action of Granzyme B
Russell, JHAnn. Rev. Immunol.20:323, 2002
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Focal Delivery of Effector Molecules TCR : MHC-peptide complexes
induces reorientation of cytoskeleton to contact site
Microtubule-organizing center (MTOC) and golgi apparatus then follows
Enhanced binding of LFA-1 (CD11a/CD18) to ICAM-1(CD54) forms a molecular seal.
Effector molecules are delivered within the sealed area
CD8
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Perforin/Granzyme is Needed to Clear CMV Infected Cells
Eur. J. Immunol. 30:1350, 2000
Mice infected with MCMV
Day 15 Day 30
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Effector Function of Th1 Cells
Th1 cells activate macrophages to induce intracellular killing of organisms that grow in vesicles
MHC class II restricted response Endosomal processing pathway
Th1 cells produce membrane-associated proteins soluble cytokines
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Effector Molecules of Th1 Cells
Membrane bound CD40 ligand - sensitizes macrophages to respond
to IFN Fas ligand - induces apoptosis of target cell
Soluble IFN- activates macrophages & MHC class I & II
and co-stimulatory molecules TNF- activates macrophages & induces NO
production GM-CSF - activates macrophages LT, TNF- - activates macrophages & induces NO
production
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Th1 Cytokines
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Leishmania: The Poster Child for Th1-mediated Infections.
Immunity 4:283, 1996
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Production of Th1 Effector Molecules
Effector molecules must be synthesized – for each killing event 1-2 hrs after TCR stimulation.
TCR receptor triggering induces Expression of CD40L Cytokines are made de novo
This process minimizes “by-stander” activation BUT FasL receptor killing is more promiscuous that
CTL granule release because it can occur in the absence of TCR stimulation.
IFN mRNA contains (AUUUA)n sequence in untranslated 3’ region that reduces the 1/2 life of mRNA
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Function of Other Th1 Effector Molecules
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Granulomas Form When Microbes Resist Th1-Mediated Killing
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Effector Function of Th2 CellsHelp B cells produce antibody
Linked recognition - T & B cells must “see” the same antigen but not identical epitopes
MHC - class II antigen presentation activates Th2 cell to express CD40L
CD40L - drives B cells into cell cycle
IL-4, IL-5, IL-10, IL-13 - drives B cell proliferation (IL-6) & differentiation
Isotype switching
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Th2 Cytokines
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Interaction Between Th2 Cells and B cells
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Focal Delivery of Effector Molecules
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CD4 T Cell Differentiation
Process that occurs following the activation of naïve CD4 cells which directs Th1 or Th2 cell development
Influenced by: Cytokines
Th1: IL-12 & IFN Th2: IL-4
Co-stimulatory molecules on APC Nature of the peptide:MHC ligand (dose, affinity)
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CD4 T Cell Differentiation
Different patterns of cytokines were produced by T cell clones R. Coffman & T. Mosmann (1986) JI 136:2348
Listeria infection of macrophages induced IL-12 production which was necessary for Th1 cell development K. Murphy (1993) Science 260:547-549
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Lysteria monocytogenes: A model for inducing Th1 Differentiation
Hsieh, C-S Science260:547, 1993
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Influence of Cytokines on T Helper Cell Differentiation
IL-4
IL-12, IL-23, IL-27 & type I IFNs
IL-4, MCP-1?
IL-12
Th1
Th2
IL-2ThP
IFNIL-2LT (TNF)
IL-4IL-5IL-10IL-13
IL-17IL-6TNFa
ThIL-17
DTH & MQactivation
Inflammatorypathology
Allergic reactions & Eosinophilic inflammation
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Th0 progresses to Th1 or Th2
PNAS 29:7565, 1995
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Cytokines signal via JAK/STAT Pathway
Jak2Tyk2↑IL-12
Jak1Jak3↑IL-4
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Cytokine Receptor Families
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Influence of Transcription Factors on T cell subset Differentiation
IL-12 APC
T-BET
IFN
IFNR
TCR
1) STAT1
2)STAT4IFNIL-23p19 chainIL-12p40
IL-12R(p40 chain)
CD4 cell
Th1
IL-18RIL-18
CXCR3
PSGL-1Receptor
Th17
CXCR5
CCL9, 10 & 11
CXCL13
IL-17
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What are the progenitors for Th17?
Bettelli, E & Kuchroo, V.K. J. Exp. Med. 201:169-171, 2005
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Influence of Co-stimulatory Molecules on Differentiation
B7.1
B7.2, Ox40ICOS, T1/ST2
Th1
Th2
IL-2
ThP
IFNIL-2LT (TNF)
IL-4IL-5IL-13
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Th1 cell Transcription Factors
Szabo, S, Cell 100:655, 2000
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Influence of Transcription Factors on Th2 Cell Differentiation
IL-4
APC
STAT6
GATA-3
C-maf (IL-4 transcription factor)
NFAT
IL-4IL-5IL-13
IL-4R
TCR
IL-12IL-12R
CD4 cell
Th2
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Expression of GATA-3 During Th2 Cell Differentiation
Immunity 9:745, 1998
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Epigenetic Regulation of T cell Differentiation
JCI 109:431, 2002
Nucleosomes/HistonesAcetylatedMethylatedPhosphorylated
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T helper Cell Differentiation
type 1 IFNs IL-23IL-27IFNIL-12
IL-4
TCR
IL-12RIL-4R
DC DC
IL-4
STAT4
STAT6T-BET
IFN
IL-18R
NFB
c-maf
GATA-3
IL-10
IFNR
STAT1
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A Dominant Th1 vs. Th2 Response Alters the Outcome of Infection
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A Dominant Th1 vs. Th2 Response Alters the Outcome of Infection
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Th1/Th2 Differentiation is linked to cell division
Immunity 9:229, 1998
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Papers for Discussion 5/12/05
P1. 1). Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ.Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.J Exp Med. 2003 Dec 15;198(12):1951-7.
P2. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005 Jan 17;201(2):233-40.