{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:46:15Z","timestamp":1792673175381,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,18]]},"group-title":"Immunology","reference-count":79,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["1R21AI190763-01A1"],"award-info":[{"award-number":["1R21AI190763-01A1"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,18]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  B cells can control inflammation, but the factors governing B cell-mediated immune regulatory network remain unclear. We report that IL-2\/CD40L enable class-switched memory (CSM) B cells to acquire an immunosuppressive phenotype characterized by the expression of surface TIGIT as well as multiple other inhibitory receptors (PD-1, LAG-3, GITR, CD39, and CTLA-4) and soluble molecules (IL-10, granzyme B, and IL-35). TIGIT\n                  <jats:sup>+<\/jats:sup>\n                  CSM B cells expressing functional CCR9 exhibit significant defects in total immunoglobulin secretion, while preserving IgA2 secretion. Furthermore, IL-2\/CD40L-induced\n                  <jats:italic>ex vivo<\/jats:italic>\n                  -generated TIGIT\n                  <jats:sup>+<\/jats:sup>\n                  CSM B cells suppress human T cell-mediated inflammation in a xenogeneic mouse model of acute graft-versus-host disease, while promoting IL-10-producing regulatory T cell (Treg) response. These findings identify IL-2\/CD40L as key drivers of a B cell-mediated immune regulatory network, especially by generating TIGIT\n                  <jats:sup>+<\/jats:sup>\n                  CSM B cells that can further promote Treg response. This study supports the development of TIGIT\n                  <jats:sup>+<\/jats:sup>\n                  B cell-based therapy models for inflammatory diseases.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"755729v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        IL-2\/CD40L can generate and maintain immunosuppressive TIGIT\n                        <jats:sup>+<\/jats:sup>\n                        B cells in humans.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        TIGIT\n                        <jats:sup>+<\/jats:sup>\n                        B cells expressing CCR9 have defects in antibody secretion, but not IgA2.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        TIGIT\n                        <jats:sup>+<\/jats:sup>\n                        B cells suppress inflammation, while promoting Treg response\n                        <jats:italic>in vivo<\/jats:italic>\n                        .\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>IL-2\/CD40L can thus build a robust B cell-mediated immune regulatory network.<\/jats:p>\n                    <\/jats:list-item>\n          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