B and T Lymphocyte Attenuator Suppresses IL-21 Production from Follicular Th Cells and Subsequent Humoral Immune Responses

Abstract

We recently showed that mice lacking B and T lymphocyte attenuator (BTLA), a third inhibitory coreceptor expressed on B cells and T cells, exhibit an increased Ag-specific IgG response and gradually develop hyper-γ–globulinemia and autoantibody production. Recent studies revealed that follicular Th (Tfh) cells, which are non-Th1, non-Th2 effector T cells that express CXCR5 and provide help for B cells to produce Ig, also express BTLA. However, the role of BTLA in Tfh cell function remains unknown. In this study, we examined the regulatory role of BTLA in the development and function of Tfh cells. We found that CXCR5+ Tfh cells expressed higher levels of BTLA than did CXCR5− conventional CD4+ T cells. We also found that adoptive transfer of BTLA−/− CD4+ T cells, stimulated under Tfh cell-inducing conditions (Tfh-like cells), to wild-type (WT) mice induced more Ag-specific IgG2a and IgG2b production compared with that of WT Tfh-like cells. By contrast, another adoptive-transfer experiment using BTLA−/− mice as recipients showed that the expression of BTLA on B cells was not involved in the regulation of Tfh-like cell-mediated Ag-specific IgG responses. Moreover, the development of IL-21–producing CXCR5+ Tfh-like cells was significantly increased in BTLA−/− CD4+ T cells compared with WT CD4+ T cells. Furthermore, Tfh-like cell-mediated IgG responses were abolished when IL-21R−/− mice were used as recipients. These results suggest that BTLA signaling suppresses IL-21 production from Tfh cells and subsequent Tfh cell-mediated IgG responses.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…In this setting, more antigen-specific IgG 2a and IgG 2b production was observed in the recipient mice that were adoptively transferred with Tfh-like BTLA-deficient cells than in the recipient mice that were adoptively transferred with WT Tfhlike cells. 35 Although the development of Tfh cells was not affected in the BTLA-deficient mice, their function was slightly augmented and, consequently, the production of antigenspecific antibodies was also slightly increased. 35 It will be necessary to reconcile the discrepancies of the slightly enhanced antibody response in autoimmune diseases and after conventional immunization of BTLA-deficient mice with the results of our investigation in the setting of fully MHCmismatched allotransplantation.…”

“…[23][24][25] The humoral immune response and propensity to develop autoimmune diseases are enhanced not only in BTLA-deficient mice 23,35 but also in HVEM-deficient mice. 48 The latter strengthens the predominant in vivo function of HVEM as an inhibitory ligand rather than a costimulatory ligand.…”

“…35 Two experimental approaches were adopted depending on the alloantigen source and the immunological technique that was chosen (membranebound H-2 d class I alloantigens expressed on the cell surface of BALB/c thymocytes for flow cytometry or recombinant-soluble biotinylated H-2K d and H-2K b monomers for ELISA), and they were used to follow the allogeneic humoral immune responses. The first strategy consisted of incubating diluted serum samples collected from recipient mice at days 10 and 20 post transplantation with donor (BALB/c) thymocytes.…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Noteworthy, the regulation of costimulatory molecule expression in the course of Tfh cell differentiation and their contribution to Tfh cell function is not fully understood. In particular, little is known about BTLA in Tfh cells except that it can dampen humoral immune responses by suppressing IL‐21 secretion by Tfh cells (Kashiwakuma et al , 2010). It is conceivable that the organ‐dependent differences in both the frequency of Tfh cells and their expression of costimulatory molecules may reflect the distinct requirements of tissue‐specific immune responses.…”

The role of the T follicular helper cells in allergic disease

“…A confounding factor may be B-and T-cell attenuator 57 that is highly expressed on CXCR5 1 Tfh cells and inhibits their capacity to produce IL-21. 58 …”