title: Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity.
abstract: CD98 H chain (4F2 Ag, Slc3a2) was discovered as a lymphocyte-activation Ag. Deletion of CD98 H chain in B cells leads to complete failure of B cell proliferation, plasma cell formation, and Ab secretion. In this study, we examined the role of T cell CD98 in cell-mediated immunity and autoimmune disease pathogenesis by specifically deleting it in murine T cells. Deletion of T cell CD98 prevented experimental autoimmune diabetes associated with dramatically reduced T cell clonal expansion. Nevertheless, initial T cell homing to pancreatic islets was unimpaired. In sharp contrast to B cells, CD98-null T cells showed only modestly impaired Ag-driven proliferation and nearly normal homeostatic proliferation. Furthermore, these cells were activated by Ag, leading to cytokine production (CD4) and efficient cytolytic killing of targets (CD8). The integrin-binding domain of CD98 was necessary and sufficient for full clonal expansion, pointing to a role for adhesive signaling in T cell proliferation and autoimmune disease. When we expanded CD98-null T cells in vitro, they adoptively transferred diabetes, establishing that impaired clonal expansion was responsible for protection from disease. Thus, the integrin-binding domain of CD98 is required for Ag-driven T cell clonal expansion in the pathogenesis of an autoimmune disease and may represent a useful therapeutic target.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726, USA. jmcantor@ucsd.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Cantor
authors.forename: Marina
authors.initials: M
authors.lastname: Slepak
authors.forename: Nil
authors.initials: N
authors.lastname: Ege
authors.forename: John T
authors.initials: JT
authors.lastname: Chang
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D002999:Clone Cells; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics*; D006801:Humans; D039641:Integrin beta Chains / Q000737:chemistry / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation
chemical_list: D027282:Fusion Regulatory Protein 1, Heavy Chain; D039641:Integrin beta Chains; C545989:SLC3A2 protein, human; C523212:Slc3A2 protein, mouse