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      Cytokine-skewed Tfh cells: functional consequences for B cell help

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      1 , 1 , 1 , *
      Trends in immunology

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          Abstract

          CD4 + follicular helper T (Tfh) cells play a vital role in providing help for B cells undergoing selection and differentiation into activated antibody-secreting cells in mammalian germinal centers (GCs). Increasing evidence suggests that Tfh cells are a heterogeneous population that generates cytokine-skewed immune responses – a reflection of the microenvironment during differentiation. This has important ramifications for Tfh-mediated B cell help. Because Tfh subsets can have opposing effects on GC B cell responses, we discuss current findings regarding the differentiation and functions of cytokine-skewed Tfh cells in modulating GC B cell differentiation. Antibodies are important weapons against infectious diseases but can also be pathogenic mediators in some autoimmune conditions. Since cytokine-skewed Tfh cells can influence the magnitude and quality of the humoral response, we address the roles of cytokine-skewed Tfh cells in disease.

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          Most cited references124

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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            The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

            IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naïve CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express RORgammat, and are absent in mice deficient for RORgammat or IL-6. Mice with RORgammat-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.
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              Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

              Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).
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                Author and article information

                Journal
                100966032
                22039
                Trends Immunol
                Trends Immunol
                Trends in immunology
                1471-4906
                1471-4981
                11 March 2022
                June 2021
                08 May 2021
                14 May 2022
                : 42
                : 6
                : 536-550
                Affiliations
                [1 ]Department of Pathology, University of Utah, 15 North Medical Drive, Salt Lake City, UT 84112, USA
                Author notes
                [* ]Correspondence: tracey.lamb@ 123456path.utah.edu (T.J. Lamb).
                Author information
                http://orcid.org/0000-0003-0620-3944
                Article
                NIHMS1785621
                10.1016/j.it.2021.04.006
                9107098
                33972167
                b48caf85-759c-406a-886a-7c8ece9372fc

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Immunology
                Immunology

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