CD275/ICOSL-independent germinal centers and autoantibody in autoimmune-prone RasGRP1-deficient mice (BA13P.125)

Abstract

Abstract Lymphopenia results in favorable microenvironments for the expansion and activation of autoreactive lymphocytes. Mice deficient in guanine nucleotide exchange factor Rasgrp1 (KO) are T lymphopenic early in life and develop a lymphoproliferative disorder with features of human SLE. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development as well as during germinal center responses, suggesting both T cell-independent and -dependent mechanisms are responsible. To understand whether T cells are involved in the breach of tolerance in germinal centers, we examined T effector cells in KO mice. In addition to the expected increase in Th1 cells, the frequency and number of Th17 cells were also elevated in KO mice. Th17 cells were positive for CXCR5 and Bcl-6, localized to germinal centers and upregulated levels of CD278/ICOS coordinately with the appearance of germinal centers, all attributes of T follicular helper cells (Tfh17). To determine whether CD278-CD275 interactions were required for the development of Tfh17 cells and for autoantibody, we crossed KO and CD275-deficient mice. Interestingly, KO mice lacking CD275 formed germinal centers with an elevated frequency of Th17 cells and similar titers of autoantibodies. From these data, we suggest that CD278-CD275 interactions are not required for germinal centers and autoantibody production in mice lacking RasGRP1.