Abstract
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.
Highlights
T cells express T cell receptors (TCR) that recognize antigens presented to them by the MHC and differentiate into various effector cells, which are essential for mounting defenses against pathogens [1] [2] [3]
We previously reported that an anti-CD98hc mAb that could inhibit T cell proliferation suppressed the development of type1 diabetes [13]
The proper functional differentiation of CD4+ T cells is essential for defenses against pathogens and is accompanied by T cell proliferation [1] [3] [20]
Summary
T cells express T cell receptors (TCR) that recognize antigens presented to them by the MHC and differentiate into various effector cells, which are essential for mounting defenses against pathogens [1] [2] [3]. T cell proliferation and functional differentiation are regulated by signaling through the TCR, cytokines, and co-receptor molecules [6] [3] Networks that incorporate these stimuli tightly regulate the acquisition of either effector or PLOS ONE | DOI:10.1371/journal.pone.0139692. We previously reported that an anti-CD98hc mAb that could inhibit T cell proliferation suppressed the development of type diabetes [13]. These results suggest that CD98hc is crucial for T cell-mediated adaptive immune responses. It remains unclear if CD98hc is required for the acquisition of effector functions by CD4+ and CD8+ T cells in vivo
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