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      Follicular T cells mediate donor‐specific antibody and rejection after solid organ transplantation

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          Most cited references34

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          Germinal centers.

          Germinal centers (GCs) were described more than 125 years ago as compartments within secondary lymphoid organs that contained mitotic cells. Since then, it has become clear that this structure is the site of B cell clonal expansion, somatic hypermutation, and affinity-based selection, the combination of which results in the production of high-affinity antibodies. Decades of anatomical and functional studies have led to an overall model of how the GC reaction and affinity-based selection operate. More recently, the introduction of intravital imaging into the GC field has opened the door to direct investigation of certain key dynamic features of this microanatomic structure, sparking renewed interest in the relationship between cell movement and affinity maturation. We review these and other recent advances in our understanding of GCs, focusing on cellular dynamics and on the mechanism of selection of high-affinity B cells.
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            Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response

            Follicular helper (TFH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of TFH numbers maintains self-tolerance. We describe a population of Foxp3+Blimp-1+CD4+ T cells constituting 10-25% of the CXCR5highPD-1highCD4+ T cells found in germinal center after immunization. These follicular regulatory T cells (TFR) share phenotypic characteristics with TFH and conventional Foxp3+ regulatory T cells (Treg) yet are distinct from either. Similar to TFH cells, TFR development depends on Bcl-6, SAP, CD28 and B cells; however TFR originate from thymic-derived Foxp3+ precursors, not naïve or TFH cells. TFR are suppressive in vitro and limit TFH and germinal center B cell numbers in vivo. In the absence of TFR, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, Treg cells use the TFH differentiation pathway to produce specialized suppressor cells that control the germinal center response.
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              Follicular regulatory T (Tfr) cells with dual Foxp3 and Bcl6 expression suppress germinal center reactions

              Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl6, and localized in the germinal centers in mouse as well as human. The expression of CXCR5 on Treg cells depends on Bcl6. These CXCR5+Bcl6+ Treg cells are absent in thymus but can be de novo generated from CXCR5-Foxp3+ natural Treg precursors. Lack of CXCR5+ Treg cells leads to greater germinal center reactions. These results unveil a Bcl6-CXCR5 axis in Treg cells that undermines the development of follicular regulatory T (Tfr) cells that function to inhibit the germinal center reaction.
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                Author and article information

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                Journal
                American Journal of Transplantation
                Am J Transplant
                Wiley
                1600-6135
                1600-6143
                May 2021
                February 11 2021
                May 2021
                : 21
                : 5
                : 1893-1901
                Affiliations
                [1 ]Clinical Pathology Department Faculty of Medicine Minia University Minia Egypt
                [2 ]Transplantation Research Center, Renal Division Brigham and Women’s Hospital Harvard Medical School Boston Massachusetts
                [3 ]Department of Pediatrics Division of Blood and Marrow Transplantation University of Minnesota Minneapolis Minnesota
                [4 ]Center for Transplantation Sciences Department of Surgery Massachusetts General Hospital and Harvard Medical School Boston Massachusetts
                [5 ]Department of Pathology Brigham and Women’s HospitalHarvard Medical School Boston Massachusetts
                Article
                10.1111/ajt.16484
                33421294
                7971e30d-cc5d-475e-a82e-075eef24d814
                © 2021

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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