T Helper Cells Lecture

T Cell Subsets

Yufang Shi University Professor Department of Molecular Genetics, Microbiology and Immunology UMDNJ-Robert Wood Johnson Medical School [email protected]

Major Histocompatibility Complex Antigen and T Cells

Chromosome 17 H-2 loci

K

Gene encoding Involved antigen Processing

I

95% CD8 T cells Chromosome 2

CIITA

Complement Cytokine

I-A I-E II II

D

CD4

NKT cells

I

L

Ib

I

5% CD8 T cells

β 2m

Chromosome 1

CD1.1

CD1.2

T cell subsets in MHC deficient mice

Animals

Class II

Class Ia Class Ib

T cell selected CD4, Naïve CD8,

Ib -CD8

_____________________________________________________________________ C57BL/6 + + + + + + CIITA-/-

-

+

Kb-/-Db-/-

+

-

Kb-/-Db-/-CIITA-/-

-

+

β 2m-/-

+

β 2m-/- CIITA-/-

-

+

+

+

+

-

+

+

-

-

+*

-

-

+

-

-

-

-

-

-

-

+

-

Autoimmune _ _ _ + +/_

T Cell Activation

Scharenberg et al. Nat Rev Immunol. 2007

APC MHC II

B7.1 B7.2 CD40 ICOSL ICAM-1 ICAM-2 LFA-3

CD4 T

CD4 TCR

Antigen recognition complex

CD28 CTLA4 CD40L ICOS LFA-1 CD2

Co-stimulatory pairs Adhesion pairs

Cytokine/Cytokine Receptors

The Cytokine Network

T Cell Subsets

Reciprocal Cellular and Humoral Immune Responses

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,

The Discovery of Th1 and Th2

IL-4

J. Immunol. 1986

IL-4

IL-4

Differential Expression of Cytokines by Th1 and Th2 cells Cytokine IFN-γ LT (TNFβ ) IL-2 IL-3 GM-CSF TNF-α MIP-1α MIP-1β TCA-3 IL-4 IL-5 IL-6 IL-9 IL-10 IL-13

Th1 + + + + + + + + + -

Th2 + + + + + + + + + + + +

Th0 + + + +

Thp + -

+ +

-

-

In Vitro Generation of T Helper Subsets Naïve T Cells - CD3 - CD28

-IL-4 IL-12

-IFN- IL-4

-IFN- IL-4  -IFN- IL-4 Cytokine IL-6, TGFβ depletion TGFβ v v

v v

Th1

Th2

Th(i)17

Treg

ThGM

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

Biedermann et al., J Invest Derm Sym Proc 2004

T Helper (CD4+ ) Subsets Antigen APC

IL-12

T h 0

IL-4

FasL

Suicide Fas Pro-Inflammatory Cytokines

T h 1

DR4

IFNγ IL-2 LT

Th1 response

Cellular Immunity DTH

T h TRAIL 2

Anti-Inflammatory Cytokines

IL-4 IL-10 IL-13 IL-5 IL-6

Th2 response Humoral Immunity Acute Hypersensitivity

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 Cells CON

IL-4

5.1

10 . 2

IFN-γ

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.

Th1 and Th2 Cells Do not Represent All CD4+ Cells CON

IL-4

5.1

10 . 2

IFN-γ

Th17 and Treg

Deenick and Tangye, Immunology and Cell Biology, 2009

Th17 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)

IL-17 •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-α , and chermokines

Th17 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 CD4+ T Cells (Treg)

CD25=IL-2Rα

Regulatory CD4+ T Cells (Treg) •CD4+CD25+Foxp3+  Immunosuppressive • •Anti-CD25 enhances immune response

From Bubnoff

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.

(Awasthi and Kuchroo, International Immunology, 2009)

Other T cell Subsets 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 characterized CD8+ T cells are also immunosuppressive

Complexity of Inflammatory Disorders

Bettelli et al., Nature 2008