th 细胞亚群和 t 记忆细胞 季明春 扬州大学医学院 2010-12. 2 th 细胞亚群 th1/th2...
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Th细胞亚群和 T记忆细胞
季明春
扬州大学医学院2010-12
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Th细胞亚群• Th1/Th2 cells
• Th17 Cells
• Tfh Cells
• Th9 Cells
• Treg Cells
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Th细胞亚群• Th1/Th2 cells
• Th17 Cells
• Tfh Cells
• Th9 Cells
• Treg Cells
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Introduction of Th1/Th2 cells
• In 1986, T.R. Mosman and R.L. Coffman observed that individual clones of mouse helper T cells could be separated into two classes depending upon the specific cytokines the cells secrete in response to antigenic stimulation.
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Induction of Th1 and Th2 Responses
Th2
Th1
Antigens
IL-4
IL-12IFN-γ
APC
Naïve CD4
Effector Cells
Sig
nal 2
Sig
nal 1
IL-2IFN-γ
IL-4IL-5IL-10
Cellular Immune
Responses
Humoral Immune
Responses
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CD4+T Cells CD8+T CellsTh1 Th2 Tc1 Tc2
Cytokines secretedIL-2 + - + -IL-3 + - - -IL-4 - + - +IL-5 - + - +IL-6 - + - ?IL-10 - + - ?IL-13 - + - ?a-TNF + + - -b-TNF + - + -g-IFN + - + -
EffectoractivityCytotoxicity - - + -DTH + - +/- -
Help activity IgG2a IgG1,IgE - +of B cells
Cytokines secreted by and effector activitiesof T-lymphocyte subsets
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Th1 and Th2 Differentiation in vivo
Infection of mice with Leishmania Major (利什曼原虫 ) provides a valuable model for the study of Th1 and Th2 differentiation in vivo
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Leishmania major Infection in Mice Provides a Useful Model to Study Th1 and Th2 Differentiation and Memory in vivo
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Leishmania major infection: Mouse Models
Balb/C
BL/6
Th 1 response
Death
Recovery
Th 2 response
IL-12
αIL-1
2/αI
FN-γ
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Signaling of IL-12 Receptor
1 2
TYK2
JAK2
p40p35
STAT4P
P
Y
Stat4
Stat4
PP
Y
YIFN-
Production
Expression
1: Expressed on Th1, Th2, N.K., and B cells
2: Expressed on activated Naïve T, Th1, and N.K. cells
Regulation
Enhanced by: activation of -CD28, IL-2, IL-7, IL-15, IFN- (mouse), IFN- (human)
Inhibited by: IL-4, IL-10, TGF-, PGE2, Dex
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Cytokines On Th1 Cell Development
Pathogen
APC CD4
+
T Cell
STAT4
TCR IFN-γ
IFN-γ+++
IL-27
TCCR/
WSX-1
IL-12 IL-12 IL-23
IL-12 IL-18 IL-18
Naïve CD4+ Th1 Th1 Effector
IL-12Rβ1 β2 IL-18R IL-18R
IL-12Rβ1
IL-12Rβ1
IL-12Rβ1β2
β2
STAT1 T-bet IFN-γ T-bet
STAT4STAT4
NFKBGADD45p3B
IRAKNFKB
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The Th1/Th2 Paradigm in Human Diseases (1)
Transplantation rejection and tolerance• Th1—DTH—rejection• Th2—toleranceSuccessful pregnancy and unexplained recurrent
abortion• Successful pregnancy Th2/Tho• Recurrent abortion—Th1Allergic disorders• Th2 cells—the involvement of the mast
cell/eosinophil/IgE-producing B cell in the pathogenesis of allergy
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The Th1/Th2 Paradigm in Human Diseases (2)
• Autoimmune disorders• Autoimmune thyroid diseases—Th1• Multiple sclerosis (MS)—Th1 profile• Th1 or insulin-dependent diabetes
mellitus—Th1 profile• Systemic sclerosis (SSc)—Th2 profile
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Th细胞亚群• Th1/Th2 cells• Th17 Cells——IL-17-producing T cells
• Tfh Cells
• Th9 Cells
• Treg Cells
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A new subset of Th cells—Th17
Naïve CD4+ T cell
TGF-β
IL-4
IL-23IL-6
Th17
Th1
Th2
Treg IL-6
IL-17AIL-17B
TGF-β
IL-13
IL-4IL-5
IL-12 IFN-γIFN-γ
(-)
(-)
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T(H)-17 differentiation: of mice and men
Nat Immunol. 2007, 8(9):903-5
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Th17 and diseases
• Infection
• Tumor
• Autoimmune disease Rheumatoid Arthritis(RA)
SLE
Multiple Sclerosis(MS)
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Th细胞亚群• Th1/Th2 cells
• Th17 Cells• Tfh Cells——Follicular B helper T cells
• Th9 Cells
• Treg Cells
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Lose expression of CXCR5
Naïve T cells: CXCR5-
CXCR5 is transiently upregulated on CD4+ T cells following activation
Retain CXCR5 expression
Th1/Th2 Th17/Treg differentiation
TFH cells
Origin of TFH cells
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Follicular helper T cells: Lineage and locationImmunity 30, March 20, 2009
First contact between pMHC -specific effector TⅡ FH cells and antigen- primed pMHCⅡ+ B cells occurs at the T-B borders.
Pre-GC effector TFH cells
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TFH cells and autoimmunity
Human SLE patients : an increased frequency of ICOS+CD4+ T cells in their peripheral blood.
Lupus-prone mice: an increased frequency of ICOS+CD4+ T cells in spleens.
Chronic inflammation: TFH cells may also promote chronic inflammation.
Any dysregulation of T cell function or tolerance induction can have a significant effect on the selection of Ab specificities:
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TFH cells and immunodeficiencies
Ineffective T cell help to B cells appears to underlie certain humoral
immunodeficiencies.
X-linked lymphoproliferative disease (XLP)
ICOS deficiency
CVID
It is likely that compromised development or function of TFH cells contributes to impaired B cell differentiation and humoral immunity in conditions of immunodeficiency.
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Th细胞亚群• Th1/Th2 cells
• Th17 Cells
• Tfh Cells• Th9 Cells——IL-9-producing T cells
• Treg Cells
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Introduction
Recently, two reports described a discrete subset of interleukin-9(IL-9)-producing T cells that might be closely related to the TH2-cell lineage.
These IL-9-producing T cells seem to be a distinct population that does not show the characteristics of other described T-cell subsets------“TH9” cells.
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TGF-β deviates TH2 cells to a “TH-9” fateIL-9-producing T cells could be generated from TH2 cells that
were exposed to TGF-β in vitro, even when the TH2 cells were highly polarized.
×IL-4 inhibits TGF-β-induced Foxp3+ T cellsIL-4 actively inhibits the induction of Foxp3 in the presence of TGF-β.
The inhibition of Foxp3 expression by IL-4 is mediated through the IL-4-STAT6 pathway.
The Foxp3 can directly interact with GATA-3 and this association inhibits GATA-3 mediated transactivation of IL-5, which is one of its target genes.
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Function of IL-9+ T cells
IL-9 is involved in immunity against helminths and is important for recruiting mast cells to the site of infection.
Lower levels of IL-9 production correlated with decreased mast-cell recruitment and impaired immunity against the helminth Trichuris muris.
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TH9 cells lack suppressive function and promote tissue inflammation.
◆ TH9 cells also produced IL-10. However, unlike IL-10-producing Tr1 cells,TH9 cells do not have any suppressive effects in vitro but readily proliferate and thus act like effector T cells.
◆ Adoptive transfer of IL-9+ IL-10+ T cells into
recombination- activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9+ IL-10+ T cells were transferred with CD45RBhi CD4+ effector T cells.
Function of IL-9+ T cells
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Th细胞亚群• Th1/Th2 cells
• Th17 Cells
• Tfh Cells
• Th9 Cells
• Treg Cells
——Suppressor or Regulatory T Cells
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Introduction
• Regulation of immune responses to
self-antigen is a complex process
– Maintaining self-tolerance
– Retaining the capacity to mount immune
responses against invading
microorganisms
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Discovery of Suppressor T Cells
• In 1995, Sakaguchi et al made the seminal observation:
• The transfer of CD4+ T cells which had been depleted of the minor subpopulation (10%) of cells to nu/nu recipients induced organ-specific autoimmune diseases in the majority of recipients.
• The minor subpopulation of cells are CD4+CD25+ T cells.
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CD4+CD25+Tr cells• Constitutively express the IL-2R-α (CD25)• Glucocorticoid induced tumor necrosis factor receptor (GI
TP)• 5-10% of the peripheral T cell pool• The regulatory effect by a mechanism dependant on cell-
cell contact • Expression of the inhibitory co-stimulatory molecule CTL
A-4• Cell surface TGF-β or release IL-10
• Foxp3, master regulatory gene
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Overview of phenotypes and functions of CD4+ T cells
NaïveCD4
Th1
Tr
Th2
IFN-γCell mediated immune
responses
IL-4 IL-5 IL-10 IL-13
humoral immune response
Tr 1
Th 3
CD4+
CD25+
High IL-10 , low TGF-β
TGF-β
cell-cell contact
Natural Tr in thymus contact-dependent
Adaptive Tr in peripheral lymphoid tissue cytokines-dependant
Regulatory T cells
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Differentiation of Tr cells
Naïve CD4+
T cells
Tr1
Th3
CD4+CD25
TGF-β
TGF-β
IL-10 + IFN-α_
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Primary function of Tr cells
• Maintaining self-tolerance and homeostasis
• Preventing infection-induced immunopathology
• Prolong pathogen persistence by suppressing protective Th1 responses
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Generation of Tr1 cells
OVA-TCR
Naïve CD4
Tr1 cells
IL-10 IL-5 +TGF-β
OVA + IL-10Immunosuppressive drugsAnti-IL-4 + Anti-IL-12
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Phenotype and function of Tr 1 cells
• Expression CCR5 and TS-STL• Immunosuppressive properties: - prevent the development of Th1 mediated autoimmune disease - suppress immune response to pathogens, tumors and allo antigens - suppress of proliferative responses and cytokine production• The suppressive effects of Tr1 cells are reversed
by neutralizing IL-10
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Th3 cells
• Secrete TGF-β
• Suppress the induction of experiment autoimmune encephalomyelitis (EAE).
• Suppress the induction of protective tumor-specific cytotoxin T lymphocyte (CTL) responses
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What is the target cell for CD25+ T-cell-mediated suppression?
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What is the target cell for CD25+ T-cell-mediated suppression?
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记忆性 T细胞
Memory T cell Differentiation and Memory Generation
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Immune response and generation of memory cells
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Phase of memory
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Generation of CD4+ effector T cells
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Subsets of Th1 cells with different cytokine profiles are related to protection and memory cell generation
CCR7+ ( central memory cells )
secondary
stimulationIFN-γ-producing cells
● Lower in expression of CCR7, Effector memory cells
● Mediating protection against infections
● Apoptosis
● Would be more limited in mediating optimal and sustained protection ● Apoptosis
● Reservoir of long-term central memory cells● Unlikely to the sufficient for optimal protection
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Generation of CD8+ effector T cells
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Characterization of naïve, effector and memory T cells in humans
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Characterization of naïve and memory T cells by the expression of surface molecules
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Differentiation model for memory T cells(1)
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Differentiation model for memory T cells(1)
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Differentiation model for memory T cells(1)
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Concept of memory
• The ability to remember the specific antigen and generate faster, stronger response against re-infection
• More antigen-specific T cells
• Faster and greater response
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Features of memory
• Shorter latency period
• Faster response
• Higher magnitude
• Longer persistence time
• Key feature of immune system
• Basis for vaccine design