T细胞亚群及记忆细胞

Th2
GATA-3 STAT-6
CrTh2
iTreg
Foxp3
IL-4,5,10 抗胞外病原体 IL-13,25 (寄生虫)免疫
TGF- IL-35 IL-10
免疫负调节 和免疫耐受
过高引起过敏性 炎症和哮喘
过高或过低与肿瘤 或自身免疫病相关
CXCR5
Th17
RORt CCR4,6
Tfh
Bcl-6 STAT-3 CXCR5
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.
Chronic inflammation: TFH cells may also promote chronic inflammation.
TFH cells and immunodeficiencies
Ineffective T cell help to B cells appears to underlie certain humoral immunodeficiencies.
二、Tfh细胞表面标记、分化 及发育
初始T细胞 CCR7
发育分化
趋化因子受体
所需细胞因子 和转录因子表达
产生 细胞因子
正常免疫功能
异常时发生疾病
Th1
T-bet CXCR3
CCR5
IFN- IL-2 LT
抗胞内病原体
过高引起器官特
(病毒、细菌)免疫 异性自身免疫病
抗原刺激 后T细胞
TGF- IL-2
×
IL-4 inhibits TGF-β-induced Foxp3+ T cells IL-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.
Vogelzang) 细胞亚群
T细胞的发现
免疫/造血干细胞 过继转移技术
T细胞克隆技术
相关细胞因子的 发现、克隆和检测
Trafficking分子 (CXCL13/CXCR5)
共刺激分子(ICOS等)
实验动物学(基因 敲除, 建立Sanroque 遗传突变小鼠)
IL-21 转录因子Bcl-6
T细胞辅助B细胞——40年研究历史
三、Tfh细胞迁移、定位和功 能
外周循环
外周淋巴器官
初始T 初始T
CCR7
T细胞区
淋巴小结和生发中心
IL-21
IL-6
IL-21
IL-21R
IL-6R
IL-21R
HEV
CXCR5 CXCL13
CXCR5
CCL21 IL-21R CCR7
CD4+T
ICOS
活化T STAT-3
IL-6R
IL-6R IL-6 TCR CD28
CD40L
Tfh
BTcflh-6
STAT-3
CD28TCR
CXCL13
ICOS
CD40
TCR
CD28
B7 pMHC II ICOSL
pMHC II
B7
IL-21 IL-21R
B细胞
浆细胞
APC
BCR
CXCR5 CXCL13
B细胞增殖分化 Ig类别转换 Ig亲和力成熟
FDC
(1)
(2)
(3)
(4)
(5)
• Investigation of the “fine” lymphocyte subsets is necessary to understand the mechanisms of immunological disease and protection.
Cytokines On Th1 Cell Development
Rheumatoid Arthritis(RA) SLE Multiple Sclerosis(MS)
Tfh Cells
Follicular B helper T cells
一、Th辅助B细胞产生针对 TDAg的抗体
1966年 B细胞针对 (Claman) T细胞依赖抗原
1968年 产生抗体需要 (Miller) T细胞辅助
（4）高表达CXCR5 B细胞从T细胞区迁移到B细胞滤泡（未显示），Tfh-B细 胞相互作用，CD40L/CD40和ICOSL/ICOS共刺激分子以及Tfh分泌IL-21， 在Tfh辅助B细胞中发挥关键作用；
（5）活化B细胞发生增殖分化、Ig类别转换和亲和力成熟。
四、T细胞和B细胞在何处、如何 识别
Interleukin-9 (IL-9)-producing T cells (Th9 Cells)
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.
T-bet
IFN-γ+++
STAT4
IL-12Rβ1
IL-12Rβ1
β2
β2
IL-12Rβ1
IL-12
IL-12
IL-23
A new subset of Th cells—Th17
Th1 IL-12 IFN-γ
Naïve CD4+ T cell
IL-6 TGF-β IL-23
Th17 Treg
Th2 IL-4
TFH cells and autoimmunity
Any dysregulation of T cell function or tolerance induction can have a significant effect on the selection of Ab specificities:
TGF-β deviates TH2 cells to a “TH-9” fate
IL-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.
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.
Function of IL-9+ T cells
TH9 cells lack suppressive function and promote tissue inflammation.
◆ TH9 cells also produced IL-10. However, unlike IL-10producing Tr1 cells,TH9 cells do not have any suppressive effects in vitro but readily proliferate and thus act like effector T cells.
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.
These IL-9-producing T cells seem to be a distinct population that does not show the characteristics of other described Tcell subsets------“TH9” cells.
1986年
发现Th1和
(Mosmann和 Th2(Th2细胞
Coffman ) 分泌IL-4活化
B细胞促进
Ig类别转换)
2000年
发现滤泡
(Schaerli和 B辅助性
Breitfeld) T细胞(Tfh)
2008年 确定Tfh是
(King, Vinuesa, Nurieva,
一个独立的 CD4+T效应
（3）活化T细胞表达高水平ICOS、IL-6R、IL-21R和CXCR5，IL-6和IL-21调节 Tfh细胞分化时通过其受体激活STAT3，表达有CXCR5的Tfh被滤泡基质 细胞（包括FDC、血管细胞和网状细胞）产生的BCA-1（B cell attracting chemokine）/CXCL13趋化迁移到淋巴小结，进一步形成生发中心；
IL-17 IL-21 IL-22
IL-21 IL-10
抗胞外细菌和
过高引起炎症性
真菌免疫和炎症 疾病(EAE、CIA等)
辅助B细胞 产生抗体
过高引起抗体相关 自身免疫病 过低引起免疫缺陷
根据King C(Annu Rev Immunol 2008)修改
CD4+T细胞亚群的分化与转录因子、趋化因子受体以及分泌细胞因子的关系
T细胞亚群及记忆细胞
Introduction
• More than 100 functionally distinct populations of lymphocytes can be identified in the peripheral blood of humans.
• It is no longer tenable to study immunerelated effects using “bulk” lymphocytes populations such as “memory CD8+ T cells”.
IFN-γ
(-)
IL-17A IL-17B IL-6
TGF-β
(-)
IL-4 IL-5 IL-13
T(H)-17 differentiation: of mice and men
Nat Immunol. 2007, 8(9):903-5
Th17 and diseases
• Infection • Tumor • Autoimmune disease
IL-12
Naïve CD4+
Th1
IL-18
Th1 Effector
IL-18
IL-12Rβ1 β2
APC
TCR
STAT4
CD4+ T Cell
TCCR/ WSX-1
IL-27
Pathogen
IL-18R
IRAK NFKB
STAT1
IFN-γ
ቤተ መጻሕፍቲ ባይዱ
T-bet IFN-γ STAT4
IL-18R
NFKB GADD45 p3B
Tfh细胞的分化、迁移和组织定位
注:（1）由外周淋巴器官T细胞区高内皮微静脉（HEV）产生的SLC （secondary-lymphoid tissue chemokine）/CCL21招引表达CCR7的 初始T细胞从外周循环进入T细胞区；
（2）T细胞与成熟树突状细胞（mDC）等APC相互作用后表达IL-6R和IL-21R， APC产生的IL-6与经抗原刺激后T细胞IL-6R结合；
TD-Ag的T/B细胞表位
Fazilleau N, et al. Immunity 30, March 20, 2009
signaling lymphocyte activation molecule (SLAM) Immunity 30, March 20, 2009
原来的Th1、Th2和其它T细胞亚群对 B细胞仍有辅助作用，包括在滤泡内和其 他淋巴组织，取决于趋化因子受体的种类 和密度以及迁移能力。