CD82 promotes CD8+ T cell immune responses by mediating T cell polarization and immunological synapse formation

Abstract

Abstract Tetraspanin family proteins form a rigid membrane structure called tetraspanin-enriched microdomain (TEM) on the plasma membrane and regulate multiple cellular processes. CD82, a tetraspanin protein, is highly expressed in various immune cells, but its role in immune responses has been poorly understood. In this study, we investigated the role of CD82 in T cells using CD82 knock-out (KO) mice. At steady state, CD82 KO mice had less memory CD8+ T cells in secondary lymphoid organs compared to wild type mice, which became more pronounced in aged mice. Upon in vitro T cell receptor (TCR) stimulation, CD82 KO CD8+ T cells showed defects in phosphorylation of TCR downstream signaling molecules, activation marker expression, proliferation, and cytokine production. By confocal immunofluorescence imaging, we found that TCR stimulation-induced translocation of the microtubule organizing center and formation of the immunological synapse was impaired in CD82 KO T cells. CD82 seems to recruit T cell polarity-regulating molecules such as Scribble via the PDZ domain-binding motif located in its C-terminus and mediate the T cell polarization. In association with the defective CD8+ T cell activation caused by CD82 deficiency, CD82 KO CD8+ T cells show less efficient anti-tumor immune responses than wild-type cells when transferred to tumor-bearing mice. Collectively, our study demonstrates that CD82 mediates the T cell polarization and is required for the optimal CD8+ T cell effector function.