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T Cell Subsets

Yufang ShiUniversity Professor

Department of Molecular Genetics, Microbiology and Immunology

UMDNJ-Robert Wood Johnson Medical Schoolshiyu@umdnj.edu

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Major Histocompatibility Complex Antigen and T Cells

I I III II

K D LGene encoding

Involved antigen

Processing 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 II

K D LGene encoding

Involved antigen

Processing 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 ClassIa Class Ib T cell selectedCD4, Nave 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

B7.1B7.2

CD40ICOSL

CD28CTLA4CD40LICOS

Co-stimulatory

pairs

ICAM-1ICAM-2LFA-3

LFA-1CD2

Adhesion pairs

Cytokine/CytokineReceptors

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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 antibodyresponse (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 ThpIFN- + - + -LT (TNF ) + - -IL-2 + - + +IL-3 + + + -GM-CSF + + + -TNF- + +MIP-1 + +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

Nave 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 response

Humoral ImmunityAcute Hypersensitivity

IL-4

IL-10IL-13

IL-5

IL-6

Anti-InflammatoryCytokines

Th2TRAIL

IL-4Th0

IFN-IL-2

LT

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 DiseaseInfections

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

.0 2

.1

CO N

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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.0 2

.1

CON

IL

-4

IFN-

Th1 and Th2 Cells Do not Represent All CD4Th1 and Th2 Cells Do not Represent All CD4++ CellsCells

Th17 and TregTh17 and Treg

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Th17 and TregTh17 and Treg

Deenick and Tangye, Immunology and Cell Biology, 2009

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Produced by Th17, require the presence IL23 produced

by APC.

IL-17AF (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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Th17 and DiseasesTh17 and Diseases

Autoimmune disease:

Rheumatoid arthritis (CIA).

Multiple sclerosis (EAE)Inflammatory bowel disease aPsoriasis

High Th17 cells. IL-17 induce the production of IL-6, IL-8 and TNF-

Infections:Important for both intracellularand extracellular pathogens.IL-17 up-regulatesspecific chemokines, pro-inflammatory cytokinesand colony-stimulatingfactors (CSFs), thereby helping to induceneutrophils and othermyeloid cells recruitment at the site of infection.

Bacterial: Mycobacteria and

Pneumocystis cariniiFungal: candidiasisViral: 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 thepresence of IL-23 did not induce thegeneration of Treg or Th17 cells.Supplementation of TGF- in the

culture induced the generation ofFoxp3+ Treg cells while the addition ofIL-6 not only inhibited the induction ofTGF--induced Foxp3 but alsoconcomitantly induced the generationof Th17 cells.

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Th3: Produce TGF-b, but not IL-4 or IFN-g.

CD8+T cells: Cytotoxic

Can 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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Bettelli et al., Nature 2008