CD160 Stimulates CD8+ T Cell Responses and Is Required for Optimal Protective Immunity to <i>Listeria monocytogenes</i>

Abstract

CD160 promotes NK cell cytotoxicity and IFN-γ production, but the function of CD160 on CD8⁺ T cells remains unclear with some studies supporting a coinhibitory role and others a costimulatory role. In this study, we demonstrate that CD160 has a costimulatory role in promoting CD8⁺ T cell effector functions needed for optimal clearance of oral <i>Listeria monocytogenes</i> infection. CD160^-/- mice did not clear oral <i>L. monocytogenes</i> as efficiently as wild type (WT) littermates. WT RAG^-/- and CD160^-/- RAG^-/- mice similarly cleared <i>L. monocytogenes</i>, indicating that CD160 on NK cells does not contribute to impaired <i>L. monocytogenes</i> clearance. Defective <i>L. monocytogenes</i> clearance is due to compromised intraepithelial lymphocytes and CD8⁺ T cell functions. There was a reduction in the frequencies of granzyme B-expressing intraepithelial lymphocytes in <i>L. monocytogenes</i>-infected CD160^-/- mice as compared with WT littermate controls. Similarly, the frequencies of granzyme B-expressing splenic CD8⁺ T cells and IFN-γ and TNF-α double-producer CD8⁺ T cells were significantly reduced in <i>L. monocytogenes</i>-infected CD160^-/- mice compared with WT littermates. Adoptive transfer studies showed that RAG^-/- recipients receiving CD160^-/- CD8⁺ T cells had a higher mortality, exhibited more weight loss, and had a higher bacterial burden compared with RAG^-/- recipients receiving WT CD8⁺ T cells. These findings demonstrate that CD160 provides costimulatory signals to CD8⁺ T cells needed for optimal CD8⁺ T cell responses and protective immunity during an acute mucosal bacterial infection.