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T Cell Subsets
Yufang ShiUniversity Professor
Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School
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Major Histocompatibility Complex Antigen and T Cells
I I III IIK D L
Gene encoding Involved antigenProcessing I-A I-E
Complement Cytokine
Chromosome 17 H-2 loci
95% CD8 T cells CD4 5% CD8 T cells
CD1.1
Chromosome 1
CD1.2
NKT cells
IbCIITA
I I III IIK D L
Gene encoding Involved antigenProcessing I-A I-E
Complement Cytokine
Chromosome 17 H-2 loci
CD1.1
Chromosome 1
CD1.2
IbCIITA
Chromosome 2 2m
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T cell subsets in MHC deficient mice
Animals Class II Class Ia Class Ib T cell selectedCD4, Naïve CD8, Ib-CD8
_____________________________________________________________________C57BL/6 + + + + + +
CIITA -/- - + + - + +
Kb-/-Db-/- + - + + - +
Kb-/-Db-/-CIITA-/- - + + - - +*
2m-/- + - - + - -
2m-/- CIITA-/- - - - - - -
Autoimmune
_
_
_
+
+/-
_
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Scharenberg et al. Nat Rev Immunol. 2007
T Cell Activation
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APC CD4 T
MHC II TCR
CD4
Antigen recognition complex
B7.1B7.2CD40ICOSL
CD28CTLA4CD40LICOS
Co-stimulatory pairs
ICAM-1ICAM-2LFA-3
LFA-1CD2
Adhesion pairs
Cytokine/Cytokine Receptors
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The Cytokine Network
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T Cell Subsets
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Rats injected with repeated doses of flagellin (Salmonella adelaide) varying in doses developed specific antibody response (purple squares) and delayed-type hypersensitivity (DTH; red squares), Parish and Liew, 1972,
Reciprocal Cellular and Humoral Immune Responses
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The Discovery of Th1 and Th2
J. Immunol. 1986
IL-4IL-4IL-4
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Cytokine Th1 Th2 Th0 Thp
IFN- + - + -
LT (TNF
+ - -
IL-2 + - + +
IL-3 + + + -
GM-CSF +
+ + -
TNF- + +
MIP- + +
MIP-1 + +
TCA-3 + +
IL-4 - + + -
IL-5 - + + -
IL-6 - +
IL-9 - +
IL-10 - + -
IL-13 - +
Differential Expression of Cytokines by Th1 and Th2 cells
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In Vitro Generation of T Helper Subsets
Naïve T Cells
Th1 Th2
-IFN-IL-4
-IL-4IL-12
- CD3- CD28
Treg
Cytokinedepletion
Th(i)17
-IFN- IL-4IL-6, TGF
vv
-IFN- IL-4TGF
vv
ThGM
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Biedermann et al., J Invest Derm Sym Proc 2004
The role of transcription factors in the differentiation of TH1 and TH2 cells
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T Helper (CD4+ ) Subsets
Th2 responseHumoral Immunity
Acute Hypersensitivity
IL-4IL-10IL-13IL-5IL-6
Anti-InflammatoryCytokines
Th2TRAIL
IL-4
Th0
IFN-IL-2LT
Pro-InflammatoryCytokines
Th1
FasL
DR4
Th1 responseCellular Immunity
DTH
Suicide
Fas
Antigen
APC
IL-12
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Th1/Th2 and Diseases
•Autoimmune Diseases
Th1-organ specific: Arthritis, type I diabetes, Uveitis , Inflammatory bowl disease (IBD)
Th2-systemic: Systemic Lupus Erythematosus Chrones Disease •Infections
Th1-Intracellular: Leishmania major, Mycobacteria.
Th2-Extracellular: Worms, most bacteria
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Analysis of Th1 and Th2 CellsAnalysis of Th1 and Th2 Cells
10.2
5.1
CON
IL- 4
IFN-
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Cell Surface Markers on Th1, and Th2.
1. CD27 is negatively expressed on Th2 cells.
2. CD30 is preferentially expressed on Th2 cells.
3. IL-12Rb2 expressed on Th1
4. IFN-gRb expressed on Th2
5. CCR3 preferentially expressed on Th2.
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10.2
5.1
CON
IL- 4
IFN-
Th1 and Th2 CellsTh1 and Th2 Cells Do not Represent All CD4 Do not Represent All CD4++ Cells Cells
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Th1Th177 and and TregTreg
Deenick and Tangye, Immunology and Cell Biology, 2009
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Th1Th177 Differentiation Differentiation
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Steps in the generation of Th17 cells.
The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differentiation pathway. Th17 cells produce IL-21, which further amplifies Th17 generation in an autocrine manner. IL-21 also induces the IL-23R on differentiated Th17 cells to make them responsive to IL-23 signaling. IL-23 stabilizes the Th17 phenotype by secreting IL-17A, IL-17F and IL-22 and helping Th17 cells to acquire effector functions. STAT-3 plays an important role in Th17 differentiation, amplification and stabilization as IL-6, IL-21 and IL-23 signals through STAT-3.
(Awasthi and Kuchroo, International Immunology, 2009)
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•Produced by Th17, require the presence IL23 produced by APC.
•IL-17A–F (5 members)
IL-17A, prototype disulfide-linked homodimer IL-17F, homodimer or hetrodimer with IL-17A.
•Activation of IL-17R induces the production of cytokines such as IL-1, IL-6 and TNF- and chermokines
IL-17IL-17
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Th1Th177 and Diseases and Diseases
• Autoimmune disease: Rheumatoid arthritis (CIA).
Multiple sclerosis (EAE) Inflammatory bowel disease a Psoriasis High Th17 cells. IL-17 induce the production of IL-6, IL-8 and TNF-
•Infections: Important for both intracellular and extracellular pathogens. IL-17 up-regulates specific chemokines, pro-inflammatory cytokines and colony-stimulating factors (CSFs), thereby helping to induce neutrophils and other myeloid cells recruitment at the site of infection. Bacterial: Mycobacteria and Pneumocystis carinii Fungal: candidiasis Viral: HIV and others
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Regulatory CD4Regulatory CD4++ T Cells (Treg) T Cells (Treg)
CD25=IL-2R
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Regulatory CD4Regulatory CD4++ T Cells (Treg) T Cells (Treg)
•CD4+CD25+Foxp3+ Immunosuppressive
•Anti-CD25 enhances immune response
From Bubnoff
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(Awasthi and Kuchroo, International Immunology, 2009)
Reciprocal generation of Treg and Th17 cells
Activation of naive T cells in the presence of IL-23 did not induce the generation of Treg or Th17 cells. Supplementation of TGF-β in the culture induced the generation of Foxp3+ Treg cells while the addition of IL-6 not only inhibited the induction of TGF-β-induced Foxp3 but also concomitantly induced the generation of Th17 cells.
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Th3: Produce TGF-b, but not IL-4 or IFN-g.
CD8+ T cells: CytotoxicCan also be differentiated into Tc1, Tc2…,.CD8+Foxp3+ cells have not been characterizedCD8+ T cells are also immunosuppressive
Other T cell Subsets
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Complexity of Inflammatory Disorders
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Bettelli et al., Nature 2008