T Cell Subsets

Yufang ShiUniversity Professor

Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School

shiyu@umdnj.edu

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

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

_

_

_

+

+/-

_

Scharenberg et al. Nat Rev Immunol. 2007

T Cell Activation

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

The Cytokine Network

T Cell Subsets

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

The Discovery of Th1 and Th2

J. Immunol. 1986

IL-4IL-4IL-4

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

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

Biedermann et al., J Invest Derm Sym Proc 2004

The role of transcription factors in the differentiation of TH1 and TH2 cells

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

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

Analysis of Th1 and Th2 CellsAnalysis of Th1 and Th2 Cells

10.2

5.1

CON

IL- 4

IFN-

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.

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

Th1Th177 and and TregTreg

Deenick and Tangye, Immunology and Cell Biology, 2009

Th1Th177 Differentiation Differentiation

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)

•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

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

Regulatory CD4Regulatory CD4++ T Cells (Treg) T Cells (Treg)

CD25=IL-2R

Regulatory CD4Regulatory CD4++ T Cells (Treg) T Cells (Treg)

•CD4+CD25+Foxp3+ Immunosuppressive

•Anti-CD25 enhances immune response

From Bubnoff

(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.

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

Complexity of Inflammatory Disorders

Bettelli et al., Nature 2008