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T Cell Subsets

Yufang Shi
University Professor
Department of Molecular Genetics, Microbiology and Immunology
UMDNJ-Robert Wood Johnson Medical School
shiyu@umdnj.edu
Major Histocompatibility Complex Antigen and T Cells

Chromosome 17 H-2 loci


Gene encoding CIITA Complement Cytokine

K
Involved antigen
Processing I-A I-E D L Ib
I II II I I

95% CD8 T cells CD4 NKT cells 5% CD8 T cells

Chromosome 2 b2m
Chromosome 1
CD1.1 CD1.2
T cell subsets in MHC deficient mice

Animals Class II Class Ia Class Ib T cell selected Autoimmune


CD4, Naïve CD8, Ib-CD8
_____________________________________________________________________
_
C57BL/6 + + + + + +
_
CIITA -/- - + + - + +
Kb-/-Db-/- + - + + - + _

Kb-/-Db-/-CIITA-/- - + + - - +* +

b 2m-/- + - - + - - +/-

_
b2m-/- CIITA-/- - - - - - -
T Cell Activation

Scharenberg et al. Nat Rev Immunol. 2007


APC CD4 CD4 T
MHC II
Antigen recognition
TCR
complex

B7.1 CD28
CTLA4
Co-stimulatory
B7.2
CD40 CD40L pairs
ICOSL ICOS

ICAM-1 LFA-1 Adhesion pairs


ICAM-2 CD2
LFA-3

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 IL-4 IL-4

J. Immunol. 1986
Differential Expression of Cytokines by Th1 and Th2 cells

Cytokine Th1 Th2 Th0 Thp


IFN-g + - + -
LT + - -
(TNFb)
IL-2 + - + +
IL-3 + + + -
GM-CSF + + + -

TNF-a + +
MIP-1a + +
MIP-1b + +
TCA-3 + +
IL-4 - + + -
IL-5 - + + -
IL-6 - +
IL-9 - +
IL-10 - + -
In Vitro Generation of T Helper Subsets

Naïve T Cells
- CD3
- CD28

-IL-4 -IFN- -IFN- IL-4 -IFN- IL-4 Cytokine


IL-12 IL-4 IL-6, TGFb TGFb depletion

vv vv

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-4
Th0
IL-12

Suicide FasL

Fas Th2
Th1 TRAIL
DR4 Anti-Inflammatory
Pro-Inflammatory
Cytokines Cytokines
IL-4
IFN-g
IL-10
IL-2
IL-13
LT
IL-5
Th1 response IL-6
Cellular Immunity Th2 response
DTH 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

5.1

IL-4
10.2

IFN-g
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

5.1

IL-4
10.2

IFN-g
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-a, 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-2Ra
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

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