Loss of T cell CD98hc specifically ablates T cell clonal expansion and protects from autoimmunity. (102.16)

Abstract

Abstract CD98hc (CD98 heavy chain, 4F2 antigen, Slc3a2) is a lymphocyte activation antigen with unclear function in T cells. Deletion of CD98hc in B cells leads to complete failure of B cell proliferation, plasma cell formation, and antibody secretion. Here we examined the role of T cell CD98 in protective and auto- immune responses by specifically deleting it in mouse T cells. Deletion of T cell CD98 prevented experimental autoimmune diabetes associated with reduced T cell clonal expansion. However, initial T cell homing to pancreatic islets was unimpaired. In contrast to B cells, CD98-null T cells showed only moderately impaired antigen-driven proliferation in vitro and nearly normal homeostatic proliferation. Furthermore, these cells were activated by antigen and produced cytokines (CD4) and efficiently killed targets (CD8). The integrin binding domain of CD98hc was necessary and sufficient for full clonal expansion, highlighting the role of adhesive signaling in T cell proliferation and autoimmune disease. When CD98-null T cells were pre-expanded in vitro, they adoptively transferred diabetes, establishing that impaired clonal expansion was responsible for protection from disease. The integrin binding domain of CD98hc is thus required for antigen-driven T cell clonal expansion in the pathogenesis of an autoimmune disease and may represent a useful therapeutic target.