Amino-bisphosphonates enhance CD8+ T cell responses to vaccine antigens through an ATRAID-dependent mechanism involving the stromal compartment 2259959

Abstract Introduction Bisphosphonates (BPs) are a family of drugs that are widely used to prevent bone resorption. Recent retrospective epidemiologic studies have found a strong association between BP use and a marked reduction in incidence and severity of respiratory viral infections. This association was not observed in patients who had received non-BP medications to prevent bone loss, raising the possibility that BPs may boost anti-viral immunity by a mechanism unrelated to their effect on bone metabolism. Indeed, experiments in mice have shown that BPs can markedly boost humoral immune responses to a variety of antigens. Methods Here, we have examined the effect of alendronate (ALD), a nitrogen containing BP, on the response of CD8+ T cells to immunization with a model vaccine consisting of chicken ovalbumin (OVA) and CpG as an adjuvant. Results Compared to OVA + CpG alone, the vaccine combined with ALD elicited a significantly higher frequency of effector CD8+ T cells in the spleen and brachial lymph nodes, and these effector cells produced more granzyme B, perforin, TNF-α and IFN-γ. To access the cytosol of target cell, highly charged amino-BPs such as ALD, require the endosomal transporter, ATRAID. Indeed, vaccine supplementation with ALD in ATRAID-/- mice failed to boost endogenous effector CD8+ T cells. Moreover, reciprocal bone marrow chimeras between wild-type and ATRAID-deficient mice revealed that the ALD-induced enhancement of effector CD8+ T cell responses depends on non-hematopoietic compartments. Conclusion These data indicate that ALD is capable of enhancing the CD8+ T cell response to exogenous antigens by a mechanism that is critically dependent on the presence of ATRAID in the stromal compartment. Off-label combination of BPs with vaccines may potentiate cytotoxic T cell responses. Funding Source Moderna, Inc.; Ragon Institute of MGH, MIT and Harvard; NIH RO1 AI155865 Topic Categories Vaccines and Immunotherapy (VAC)