Understanding the development and function of T follicular helper cells

Nurieva, Roza; Chung, Yeonseok

doi:10.1038/cmi.2010.24

Cited by 100 publications

(116 citation statements)

References 98 publications

(134 reference statements)

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“…These antibodies are generated through somatic hypermutation, class switch recombination and affinity maturation of activated B cells, processes that take place in the germinal centres (GCs) of secondary lymphoid organs and depend on cognate help provided by CD4 1 follicular B helper T (T FH ) cells [1,2]. Human T FH cells are defined by the expression of characteristic markers [3][4][5][6][7]: the transcriptional repressor Bcl-6 that directs T FH lineage commitment; the chemokine receptor CXCR5 that enables T FH cells to migrate into the B-cell follicles; the CXCR5 ligand CXCL13 that attracts further CXCR5 1 cells such as naïve B cells and early activated CD4 1 T cells; the co-stimulatory molecules, inducible co-stimulator (ICOS) and programmed cell death 1 (PD-1), which interact with their corresponding ligands on B cells; and the cytokine IL-21 that steers B-cell differentiation and antibody production. Murine T FH cells express the same panel of markers with the exception of CXCL13.…”

Section: Introductionmentioning

confidence: 99%

IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

et al. 2011

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Vc9/Vd2 T cells are a minor subset of T cells in human blood and differ from all other lymphocytes by their specific responsiveness to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a metabolite produced by a large range of microbial pathogens. Vc9/Vd2 T cells can be skewed towards distinct effector functions, in analogy to, and beyond, the emerging plasticity of CD4 1 T cells. As such, depending on the microenvironment, Vc9/Vd2 T cells can assume features reminiscent of Th1, Th2, Th17 and Treg cells as well as professional APCs. We here demonstrate that Vc9/Vd2 T cells express markers associated with follicular B helper T (T FH ) cells when stimulated with HMB-PP in the presence of IL-21. HMB-PP induces upregulation of IL-21R on Vc9/Vd2 T cells. In return, IL-21 plays a co-stimulatory role in the expression of the B-cell-attracting chemokine CXCL13, the CXCL13 receptor CXCR5 and the inducible co-stimulator by activated Vc9/Vd2 T cells, and enhances their potential to support antibody production by B cells. The interaction between HMB-PP-responsive Vc9/Vd2 T cells, IL-21-producing T FH cells and B cells in secondary lymphoid tissues is likely to impact on the generation of high affinity, class-switched antibodies in microbial infections. Key words: Bacterial infections . B cells . cd T cells . IL-21 . T FH cells IntroductionThe establishment of long-term humoral immunity depends on the production of high-affinity antibodies capable of neutralising and opsonising invading pathogens. These antibodies are generated through somatic hypermutation, class switch recombination and affinity maturation of activated B cells, processes that take place in the germinal centres (GCs) of secondary lymphoid organs and depend on cognate help provided by CD4 1 follicular B helper T (T FH ) cells [1,2]. Human T FH cells are defined by the expression of characteristic markers [3][4][5][6][7]: the transcriptional repressor Bcl-6 that directs T FH lineage commitment; the chemokine receptor CXCR5 that enables T FH cells to migrate into the B-cell follicles; the CXCR5 ligand CXCL13 that attracts further CXCR5 1 cells such as naïve B cells and early activated CD4 1 T cells; the co-stimulatory molecules, inducible co-stimulator (ICOS) and programmed cell death 1 (PD-1), which interact with their corresponding ligands on B cells; and the cytokine IL-21 that steers B-cell differentiation and antibody production. Murine T FH cells express the same panel of markers with the exception of CXCL13.While the crucial role of T FH cells in providing B-cell help is undisputed, other T-cell subsets including CD8 1 T cells, NKT cells and gd T cells contribute to the outcome of humoral immune responses [8][9][10]. gd T cells support antibody production in immunised and infected mice [11][12][13] 110 [17,18], where they are scattered throughout the T zone and clustered within GCs [8]. Early studies in lupus patients led to the isolation of human gd T-cell lines capable of inducing autoantibody production by autologous B cells [19]. Subsequent ...

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Section: Introductionmentioning

confidence: 99%

IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

et al. 2011

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“…Cytokines produced by the innate immune response are critical in shaping the adaptive immune response (reviewed in reference 4). For example, if a naive CD4 ϩ T cell encounters antigen in the presence of interleukin 12 (IL-12), it will differentiate into a Th1 effector T cell, but if it encounters IL-6 and transforming growth factor ␤ (TGF-␤) during antigen presentation, it will differentiate into a Th17 effector T cell (4). Our previous experiments with mice using intranasal or intradermal inoculation with Francisella tularensis subsp.…”

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Identification of Early Interactions between Francisella and the Host

et al. 2014

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The adaptive immune response to Francisella tularensis is dependent on the route of inoculation. Intradermal inoculation with the F. tularensis live vaccine strain (LVS) results in a robust Th1 response in the lungs, whereas intranasal inoculation produces fewer Th1 cells and instead many Th17 cells. Interestingly, bacterial loads in the lungs are similar early after inoculation by these two routes. We hypothesize that the adaptive immune response is influenced by local events in the lungs, such as the type of cells that are first infected with Francisella. Using fluorescence-activated cell sorting, we identified alveolar macrophages as the first cell type infected in the lungs of mice intranasally inoculated with F. novicida U112, LVS, or F. tularensis Schu S4. Following bacterial dissemination from the skin to the lung, interstitial macrophages or neutrophils are infected. Overall, we identified the early interactions between Francisella and the host following two different routes of inoculation.

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“…Recently, a new subset of CD4 ϩ T cells, named Tfh 4 cells, has emerged as a major player in B cell-mediated humoral immunity, especially in the germinal center reactions (1)(2)(3)(4). Tfh cells have been characterized by their expression of chemokine CXCR5, which is induced in T cells following activation and dependent on costimulatory signals, such as CD28, inducible costimulatory molecule, and OX40.…”

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confidence: 99%