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      IL-21 Regulates the Differentiation of a Human γδ T Cell Subset Equipped with B Cell Helper Activity

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          Abstract

          Vγ9Vδ2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and display pleiotropic features. Here we report that coculture of Vγ9Vδ2 cells with phosphoantigen and IL-21 leads to selective expression of the transcription repressor Bcl-6 and polarization toward a lymphocyte subset displaying features of follicular B-helper T (T FH) cells. T FH-like Vγ9Vδ2 cells have a predominant central memory (CD27 +CD45RA −) phenotype and express ICOS, CD40L and CXCR5. Upon antigen activation, they secrete IL-4, IL-10 and CXCL13, and provide B-cell help for antibody production in vitro. Our findings delineate a subset of human Vγ9Vδ2 lymphocytes, which, upon interaction with IL-21-producing CD4 T FH cells and B cells in secondary lymphoid organs, is implicated in the production of high affinity antibodies against microbial pathogens.

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          Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

          Dagmar Breitfeld, Lars Ohl, Elisabeth Kremmer … (2000)
          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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            Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function

            Patrick Schaerli, Katharina Willimann, Aloïs B. Lang … (2000)
            Leukocyte traffic through secondary lymphoid tissues is finely tuned by chemokines. We have studied the functional properties of a human T cell subset marked by the expression of CXC chemokine receptor 5 (CXCR5). Memory but not naive T cells from tonsils are CXCR5+ and migrate in response to the B cell–attracting chemokine 1 (BCA-1), which is selectively expressed by reticular cells and blood vessels within B cell follicles. Tonsillar CXCR5+ T cells do not respond to other chemokines present in secondary lymphoid tissues, including secondary lymphoid tissue chemokine (SLC), EBV-induced molecule 1 ligand chemokine (ELC), and stromal cell–derived factor 1 (SDF-1). The involvement of tonsillar CXCR5+ T cells in humoral immune responses is suggested by their localization in the mantle and light zone germinal centers of B cell follicles and by the concomitant expression of activation and costimulatory markers, including CD69, HLA-DR, and inducible costimulator (ICOS). Peripheral blood CXCR5+ T cells also belong to the CD4+ memory T cell subset but, in contrast to tonsillar cells, are in a resting state and migrate weakly to chemokines. CXCR5+ T cells are very inefficient in the production of cytokines but potently induce antibody production during coculture with B cells. These properties portray CXCR5+ T cells as a distinct memory T cell subset with B cell helper function, designated here as follicular B helper T cells (TFH).
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              A fundamental role for interleukin-21 in the generation of T follicular helper cells.

              Alexis Vogelzang, Helen M McGuire, Di Yu … (2008)
              T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 25 July 2012
                Volume: 7
                Issue: 7
                Electronic Location Identifier: e41940
                Affiliations
                [1 ]Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli Studi di Palermo, Palermo, Italy
                [2 ]Dipartimento di Discipline Chirurgiche ed Oncologiche, Università degli Studi di Palermo, Palermo, Italy
                French National Centre for Scientific Research, France
                Author notes

                Conceived and designed the experiments: FD NC G. Stassi. Performed the experiments: MPL G. Sireci MT. Analyzed the data: FD G. Stassi. Wrote the paper: FD G. Stassi.

                Article
                Publisher ID: PONE-D-12-11535
                DOI: 10.1371/journal.pone.0041940
                PMC ID: 3405033
                PubMed ID: 22848667
                SO-VID: 0e409bd9-b889-496f-b4ad-fcd3a505e73d
                Copyright © Caccamo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 13 April 2012
                Date accepted : 27 June 2012
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Immunology
                Subject: Immunity
                Subject: Adaptive Immunity
                Subject: Humoral Immunity
                Subject: Innate Immunity
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Immunity
                Subject: Adaptive Immunity
                Subject: Humoral Immunity
                Subject: Innate Immunity

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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