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.

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

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

Leishmania major Infection in Mice Provides a Useful Model to Study Th1 and Th2 Differentiation and Memory in vivo

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

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

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

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

(-)

(-)

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

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.

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

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

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

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

What is the target cell for CD25+ T-cell-mediated suppression?

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

Immune response and generation of memory cells

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Phase of memory

Generation of CD4+ effector T cells

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

Generation of CD8+ effector T cells

Characterization of naïve, effector and memory T cells in humans

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