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Upon their recognition of antigens presented by the MHC, T cell proliferation is vital for clonal expansion and the acquisition of effector functions, which are essential for mounting adaptive immune responses. The CD98 heavy chain (CD98hc,  Slc3a2 ) plays a crucial role in the proliferation of both CD4 +  and CD8 +  T cells, although it is unclear if CD98hc directly regulates the T cell effector functions that are not linked with T cell proliferation  in vivo . Here, we demonstrate that CD98hc is required for both CD4 +  T cell proliferation and Th1 functional differentiation. T cell-specific deletion of CD98hc did not affect T cell development in the thymus. CD98hc-deficient CD4 +  T cells proliferated  in vivo  more slowly as compared with control T cells. C57BL/6 mice lacking CD98hc in their CD4 +  T cells could not control  Leishmania major  infections due to lowered IFN-γ production, even with massive CD4 +  T cell proliferation. CD98hc-deficient CD4 +  T cells exhibited lower IFN-γ production compared with wild-type T cells, even when comparing IFN-γ expression in cells that underwent the same number of cell divisions. Therefore, these data indicate that CD98hc is required for CD4 +  T cell expansion and functional Th1 differentiation  in vivo , and suggest that CD98hc might be a good target for treating Th1-mediated immune disorders.

CD98 Heavy Chain Is a Potent Positive Regulator of CD4+ T Cell Proliferation and Interferon-γ Production In Vivo