T Cell Subsets

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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_at_umdnj.edu
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Major Histocompatibility Complex Antigen and T
Cells
Chromosome 17 H
-
2 loci
Chromosome 17 H
-
2 loci
CIITA
CIITA
Complement
Complement
Cytokine
Cytokine
Gene encoding
Gene encoding
Ib
Ib
Involved antigen
Involved antigen
L
L
K
D
K
D
I
-
A I
-
E
I
-
A I
-
E
Processing
Processing
I
I
I
II
II
I
I
I
II
II
NKT cells
95 CD8 T cells
CD4
5 CD8 T cells
b
Chromosome
2
2m
Chromosome 1
Chromosome 1
CD1.1
CD1.2
CD1.1
CD1.2
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T cell subsets in MHC deficient mice
Autoimmune
_ _ _ /- _
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T Cell Activation
Scharenberg et al. Nat Rev Immunol. 2007
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(No Transcript)
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The Cytokine Network
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T Cell Subsets
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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,
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The Discovery of Th1 and Th2
J. Immunol. 1986
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Differential Expression of Cytokines by Th1 and
Th2 cells
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In Vitro Generation of T Helper Subsets
Naïve T Cells
?- CD3
?- CD28
Cytokine depletion
?-IFN-? IL-4 IL-6, TGFb
?-IFN-? IL-4 TGFb
?-IFN-? IL-4
?-IL-4
IL-12
vv
vv
ThGM
Th1
Th2
Th(i)17
Treg
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The role of transcription factors in the
differentiation of TH1 and TH2 cells
Biedermann et al., J Invest Derm Sym Proc 2004
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T Helper (CD4 ) Subsets
Antigen
APC
IL-4
Th0
IL-12
FasL
Suicide
Fas
Th1
TRAIL
DR4
Anti-Inflammatory Cytokines
Pro-Inflammatory Cytokines
IL-4 IL-10 IL-13 IL-5 IL-6
IFN-g IL-2 LT
Th1 response Cellular Immunity DTH
Th2 response Humoral Immunity Acute
Hypersensitivity
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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 Cells
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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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Th1 and Th2 Cells Do not Represent All CD4 Cells
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Th17 and Treg
Deenick and Tangye, Immunology and Cell Biology,
2009
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Th17 Differentiation
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Steps in the generation of Th17 cells.
The activation of naive T cells in the presence
of TGF-ß 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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IL-17

• 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-a, and chermokines

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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

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Regulatory CD4 T Cells (Treg)
CD25IL-2Ra
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Regulatory CD4 T Cells (Treg)

• CD4CD25Foxp3 ? Immunosuppressive
• Anti-CD25 enhances immune response

From Bubnoff
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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-ß in the
culture induced the generation of Foxp3 Treg
cells while the addition of IL-6 not only
inhibited the induction of TGF-ß-induced Foxp3
but also concomitantly induced the generation of
Th17 cells.
(Awasthi and Kuchroo, International Immunology,
2009)
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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,. CD8Foxp3 cells
have not been characterized CD8 T cells are also
immunosuppressive
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Complexity of Inflammatory Disorders
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Bettelli et al., Nature 2008