Loss of T Cell CD98 H Chain Specifically Ablates T Cell Clonal Expansion and Protects from Autoimmunity

Abstract

CD98hc (CD98 heavy chain, 4F2 antigen, Slc3a2) was discovered as a lymphocyte activation antigen. 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 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 antigen-driven proliferation and nearly normal homeostatic proliferation. Furthermore, these cells were activated by antigen 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 antigen-driven T cell clonal expansion in the pathogenesis of an autoimmune disease and may represent a useful therapeutic target.

Manipulation of CD98 Resolves Type 1 Diabetes in Nonobese Diabetic Mice

“…A previous study using CD98hc-deficient T cells showed reduced T cell proliferation, but no defect in acquiring effector functions (16). This article indicated that defective T cell proliferation in CD98hc-deficient T cells is attributed to lack of the integrin-binding domain of CD98hc (16). Therefore, the suppressive effect of I-142 on T cell effector functions in our studies might suggest that the I-142 mAb influences other functions of CD98hc besides integrin activity.…”

“…Indeed, our anti-CD98hc mAb was able to suppress Ag-specific proliferation and effector functions of both CD4 + and CD8 + T cells in vitro and in vivo. A previous study using CD98hc-deficient T cells showed reduced T cell proliferation, but no defect in acquiring effector functions (16). This article indicated that defective T cell proliferation in CD98hc-deficient T cells is attributed to lack of the integrin-binding domain of CD98hc (16).…”

“…Previous articles have indicated that CD98 induces aggregation in human T cells, which is blocked by soluble b 1 integrin Abs (22), and an anti-CD98 mAb suppresses Con A-mediated murine T cell proliferation (15). Recently, Cantor et al (16) reported that deletion of the mouse CD98hc gene disturbs T cell function, suggesting that CD98hc controls Ag-specific T cell proliferation. To ascertain whether the effect of I-142 administration on the resolution of T1D in NOD mice is attributed to the inhibition of CD98hc function, we downregulated CD98hc expression by injecting CD98hc siRNA.…”

“…It has been reported that an Ab specific for mouse CD98hc is able to suppress the Con A-mediated activation of mouse T cells (15). Furthermore, a recent article has indicated that genetic deletion of CD98hc in T cells negatively impacts T cell clonal expansion and suppresses the development of experimental acute encephalomyelitis and T1D induced by adoptively transferring pathogenic T cells (16). However, it remains unclear if CD98hc will be a good target molecule for treating spontaneously progressive autoimmune diseases.…”

CD98 Regulates Vascular Smooth Muscle Cell Proliferation in Atherosclerosis

“…Rapid proliferation of other cell types such as T cells 21 and B cells 12 is dependent on CD98hc. We show in vivo that after 8 weeks of HFD, CD98hc −/− VSMC display significantly reduced proliferation and increased apoptosis (Fig.…”