?????????:T????

1
?????????T????
Institute for
Immunobiology Department of Immunology Center for
Gene Immunization and Vaccine Research Fudan
University ???021-54237362 xiaowuhong_at_fudan.edu.
cn
Shanghai, China
2
T????
??T????????????? ??T?????? ??T??????
3
T????????????????????,??????????????T??? ??T??????
?,????????????????????????????? T????????????? ??T
D-Ag????????????????
4
??T????????
5

1. TCR-CD3???

TCR???TCRaß?TCR?d???? ???? ???????????????????? ?
????V?C?,??Ig??
6
TCR-CD3??? ?T?????????CD3(?Gamma dDeltaeEpsilon
?Zeta ?Eta )????????????????,?T?????????????????T
CR?????MHC????????,CD3????T?????????
7
2. CD4?CD8??
CD4 ???????Th????????DC????? ?HIV??,?APC??MHC-I
I???????? CD8 ???????Tc????,?APC??MHC-I?? ?????
? ????T???APC?????????,????????TCR-CD3??????
8
CD4?CD8 -T??????
??T???APC????????? ??????CxCP???p56lck(Src family
tyrosine kinase LCK)???????,??T???????????
9
3. ??(??)????
?????? TCR-CD3????????1?? ??????(costimulatouy
signal)??2?? ??T??????????????CD28--CD80/86,CTLA4-
-CD80/86?????T???????
10
1?CD28?CTLA-4
T
APC
CD28
CD80/86
CTLA4
CD40L
CD40
LFA-1
ICAM-1
LFA-2
LFA-3
(intercellular adhesion molecule-1)
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T???APC??????????
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2?ICOS 3?CD40L 4?CD2 5?LFA-1?ICAM-1
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4. ??????

• ?????
• ??????
• ????

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??T??????
thymic corpuscle
15

• ???????????T???????????
• ??????(TSC)
• ????
• ????

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????(DN) ?T??(pro-T)??T??(pre-T) aßTCR- ?CD3 -
?CD4 - ?CD8 -
????(DP) aßTCR ?CD3low?CD4 ?CD8
????(SP) aßTCR ?CD3 ?CD4 aßTCR ?CD3
?CD8 ??T??,???????????????????????
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1. T?????????(positive selection)
CD4CD8T????????(??MHC??)
???MHC-I??,?????CD8T??
???MHC??????????????
???MHC-II????????CD4T??
?????????????T??????????MHC???
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2. T?????????(negative selection)
DP???????SP?T??
?TCR???????????????MHC?MHC-??????T?????????
?????????????T???? ?????
19
T????????????????
20
??T????
1)??TCR?? aßT??dT?? ???????aßT????95,??dT????1
10?aßT????????????T??,????????????
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TCRaßT?TCR?dT??
TCRaßT TCR?dT
????? 5-15,???? ?????CD2CD3 ?????
HSP?????? MHC??? Tc
TCR ?? ?? ???? MHC?? ??
????? 60-70,?????? ??CD2CD3CD4/CD8 8-17aa ??MHC T
h?Tc
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2)??T??????CD4?CD8?? CD4 T???CD8 T??
TCRaßTCD4??CD2?CD3?CD4?CD8- TCR?????MHC??
????? TH0?Th1?Th2???Tc?Ts?? TCRaßTCD8??
CD2?CD3?CD4-?CD8 TCR?????MHCI??????
??Tc?Ts??
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3)?????Th?Tc?TDTH?Ts

• Th?? ????????????,????Th0?Th1?Th2???
• Tc?? ?????IFN??IL-4?IL-5?IL-10
• Ts??
• TDTH ???CD4 Th1

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• 4)??T??????T??
• ???T????CD45RO,???T????CD45RA
• 5)NK1.1 T??
• ?TCR???????CD1?????????????

Leukocyte Common antigen
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??T????
1)??????(Th1? Th2 ? Th3?Ts ? Treg) 2)???????(CTL?T
h1??dT) 3)??????(TDTH) 4) ????T??Th17
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Multiple subsets of Treg cells
Naturally occurring CD4CD25 Treg cells
(56) GITR and Foxp3

a cellcell contact
mechanism
Antigen-induced Tr1 and Th3 cells
(IL-10) and/or (TGF-b)

ck-dependent mechanism

no specific
marker has

been identified.
Adaptively induced CD4 Treg cells
GITR and Foxp3

a cell contact dependent

or soluble factor-dependent


(other than IL-10and/or TGF-b)

mechanism
CD8 Treg cells
NKT regulatory T cells
glucocorticoid-induced TNFR family related gene
(GITR)
27
Naturally occurring CD4CD25Foxp3 Tregs
Development and function of naturally occurring
CD4CD25 FoxP3 regulatory T cells (nTregs).
Developmentbone marrow-derived CD4 T cell
precursors develop naturally into nTregs upon
beneficial TCR engagement by self-peptideMHC
complexes and Foxp3 induction in the thymus. Upon
instruction in the thymus, nTregs emigrate into
the periphery as functionally fully competent
cells. Mode of action upon TCR cross-linking,
peripheral nTregs suppress the proliferation and
IL-2 production by responder CD25CD4 or CD8 T
cells in a contact-dependent manner either (a)
directly or (b) indirectly via the APC. In
addition nTregs may (c) condition DC to become
tolerogenic and turn down the response of
conventional T cells on her part
28
Extrathymic induction and function of adaptive
regulatory T cells. Adaptive regulatory T cells
(aTregs) differentiate from naive conventional
CD4 T cells either as a result of suboptimal
antigenic stimulation by resting/immature DC,
the influence of suppressive cytokines like
IL-10, TGF-b or cell contact-dependent
interaction with activated nTregs (infectious
tolerance). Their mode of action involves both
cell contactdependent (Tr1 cells) and
contact-independent suppressive activities (Th3
cells). Through the production of IL-10 and TGF-b
they convert immature DC into tolerizing APC
29
Fig. 3 Role of Tregs in early and late stages of
microbial infections. In the stages of an immune
response against a microbial infection Tregs
behave differently. A Throughout the early phase
of the response the suppressive activity of Tregs
is turned down by effector T cell-derived IL-2
and microbial components such as TLR-ligands.
Tregs respond to the stimulation by mature DC and
proliferate.
30
b At the late stage of the response, when the
invading organism is cleared from the host, Tregs
regain their suppressive function and participate
in the silencing of the T cell response by acting
on effector T cells and DC. Possibly, this late
activity is also for the proper development
of memory T cells
31
Treg-based immune intervention strategies.
Selective manipulation of Treg function is an
emerging target for immune intervention
strategies to either boost responses in cancer
and microbial diseases or suppress those unwanted
in autoimmunity, allergy, transplantation and
pregnancy disorders. The transient depletion of
Tregs as well as their modulation by microbial
agents may allow a transient reduction of Treg
activity and enforce anti-tumor responses and
immunity against viral infections. On the other
hand their selective activation could
diminish chronic pathological immune responses
32
Generation and conversion of Treg cells in the
tumor microenvironment
Tumor cells not only provide antigenic
stimulation for T cell activation but also
interact with tumor-infiltrating innate immune
cells to secrete crucial cytokines for T-cell
differentiation. Naive CD4 T cells can be
differentiated into different subsets of CD4 T
cells, including Th1, Th2, Treg and
IL-17-producing T cells (Th17), depending upon
the strength of antigen stimulation and cytokine
milieu. It is known that combination of
suboptimal antigen stimulation with TGF-b favors
the conversion of naive T cells into Treg cells
but blocks the generation of Th1 or Th2 cells.
However, TGF-b plus IL-6 facilitate the
conversion of naive T cells into Th17 cells.
Alternatively, naturally occurring CD4CD25 Treg
cells directly derived from the thymus can
cross-react with some antigens expressed by
cancer cells, thus promoting their expansion and
accumulation in the tumor microenvironment.
33
T-helper-cell differentiation
34
Human IL-17 and IL-17R key features
a Two isoforms (long and short).
35
Therapeutic targets for autoimmune
inflammatory diseases are associated
preferentially with the IL-23/Th17 pathway
36
The pathogenic role for IL-23, not IL-12, in
mouse models of autoimmunity
Studies by Cua and co-workers have demonstrated
that disease development requires IL-23, but not
IL-12, in EAE and CIA. Compared with wild-type
susceptible mice, mice deficient for IL-23
(Il23p19/) and both IL-23 and IL-12 (Il12p40/)
failed to develop disease after antigenic
challenge, whereas mice deficient for IL-12
(Il12p35/) developed more severe disease.
37
Model of Th1 versus Th17 lineage development from
naive CD4 T cell precursors (Tn)
This model emphasizes the distinct lineages
leading to mature Th1 and Th17 effector cells
(see main body of text for details). Question
marks denote speculative or unknown aspects of
Th17 differentiation that are yet to be defined.
38
Antagonistic cytokine networks control CD4
effector T-cell differentiation
Recent studies have established that Th1 and Th2
effector cytokines, IFNg and IL-4, respectively,
potently inhibit Th17 development. Furthermore,
TGF-b, a cytokine previously implicated in Treg
development and function, appears to be required
for Th17 development, both through indirect
effects (blockade of IFNg and IL-4 production by
cells of the innate immune system) and through
direct effects on naive CD4 T-cell precursors
(Tn).
39
CD4T???????????????????
40
Diversification of CD4 T Cell Lineages
Although functional CD4 T cell development has
been dominated by the Th1-Th2 paradigm for nearly
two decades, the number of defined lineages has
now increased. The cytokines associated with
arrows indicate dominant cytokines involved in
specification of each of the indicated lineages.
The cytokines listed below each cell type
indicate key effector or regulatory cytokines
produced by differentiated cells of that lineage
or, in the case of nTreg, a contact-dependent
mechanism of suppression. Tn naive, postthymic
CD4 T cell precursors Tp thymic
precursors.Dotted lines represent less
well-defined lineage relationships.
41
Model of Branching Th17 and Adaptive Treg Lineage
Development
This model emphasizes distinct pathways leading
to mature Th17 effector cells or Foxp3 adaptive
Tregs (aTreg), induced by a common requirement
for TGF-b but differential effects of IL-6 and
IL-23. Naive CD4 T cells (Tn) activated by
antigen presented on immature DCs that do not
produce IL-6 production are induced by TGF-b to
express Foxp3 and develop into aTregs (top
panel). Tns activated bymature,TLR-activatedDCstha
t produceIL-6 are induced by TGF-b to upregulate
IL-23R and become competent for IL-17 production
and IL-23 signaling. IL-23 signaling induces
responsiveness to IL-18 and IL-1, which can act
synergistically with IL-23 to induce Th17
cytokineproduction independently
ofTCRstimulation.Alternatively, TCR stimulation
by antigen can induce Th17 cytokine production
directly, without a requirement for IL-23, IL-1,
or IL-18.Dotted lines indicate possible positive
feedback loops by which cytokine products of Th17
(IL-6) or aTreg cells (TGF-b1) may reinforce
lineage development.
42

1. CD4???T??
2. CD8???T??

43
?????Th1?Th2???????
44
(No Transcript)
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3. ???T?? 4. ????????T??(TDTH) 5. NK1.1T??
46

• ??TCR?????
• ??T???????????????
• ??T??????
• ??T?????????????
• ??TCR?dT???TCRaßT??????

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T???????????????
??T???????? ??T??????? ?????T???????
48
?????????
???? ????????????? ???? ?????????????? ????
??????????????
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??T????????
??T ???????????????

• ??????APC????MHC????
• ???????

• ??????????????????

• TCR??????MHC???
• CD4T????MHC-II???????
• CD8T????MHC-I???????

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T???APC??????
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(?)T???APC???????
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T???APC???????
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(?)T???APC??????
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TCR?APC????????
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(?)T???APC??????????
CD28/B7?LFA-1/ICAM-1?CD2/CD58?
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(?)????(immunological synapse)
???TCR????-MHC??? ?????????? ????,??????
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??T?????????
(?)T?????????
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CD4T??????
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(?)T?????????
CD28/B7 LFA-1/ICAM-1?ICAM-2 CD2/LFA-3 CD40/CD40L?
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T????????
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CD28/B7??IL-2??????? ???,T????(anergy) CTLA4?CD28?
???,?B7????CD28?20?,?????????,???????T?????????
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(?)??????T??????
IL-1?IL-2?IL-6?IL-12?????
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??T?????????????
????????????????????
????(multimerization) TCR/CD3?????CD4?CD8?CD45???
????(clustering)
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??????????? (immunoreceptor tyrosine-based
activation motif, ITAM)
Y??? L??? V??? D???? E???
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T?????????
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?????????????
(?)??????

• AP-1 (Fos?Jun)
• NF-?B
• Oct-1
• NFAT (nuclear factor of activated T cell )

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(?)T??????

• ??????
• ????????
• ??????
• MHC

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(?)T??????????

• CD4T???????
• CD8T???????

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????T?????
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1. Th1?CD4T?????

• ?????????,????Mf???????
• ????APC??MHC???????????
• ??CD8T?NK??,??????

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TH1???????????
???????? ????????? ????
??? ????
IL-2 IFN-? TNF-? GM-CSF IL-3?
???????? MHC-II????? ??
????APC??
TH1
?????? NK?? Tc?? TH??
?????? ??????
???TH
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Th1???????????
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Th1?????????????????
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2. Th2?CD4T?????

• ??Mf(?????IL-10/FasL/TGF-?)
• ??B??,??Ig????

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Th2?CD4 T???B??
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3. CD8????T?????
???????????? Activation Induced Cell Death
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CD8CTL???????
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CD8T???????????

• ??????
• ???(perforin)
• ?????caspase 10

• ??TNF

• ??????????
• FasL????Fas??????
• Caspase8? ??DNA ???

79
???-??????????
80
(No Transcript)
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T???????????????

• ???? TD-Ag
• ???? T???APC
• ???? Th/CTL(Tc)
• ?????????????
• ???
• ????
• ???????
• (delayed type hypersencitivity,
  DTH)
• ??????
• ?????????

82
??T?????
83
????T?????

• (?)??T????????T??,????????
• (?)??T??????,????????
• ?????????(activation induced cell death, AICD)
• ??????(passive cell death, PCD)

84
???????????
85

• ??T?????????????????
• ??T???????
• ?????CD4T???CD8T???
• ??T??????????