The Rab32 small GTPase is required for efficient cross-priming of CD8+ T cellsagainst cell-associated antigens by XCR1+ type 1 DCs in vivo.

Abstract

Type 1 conventional dendritic cells (cDC1s) are critical for initiating adaptive immune responses through the cross-priming of CD8 T cells against antigens from tumor or virus-infected cells. This function depends on specialized cross-presentation pathways that allow cDC1s to process phagocytosed cell debris and present peptide-MHC I complexes. In this study, we identify the small GTPase Rab32 as being highly and selectively over-expressed in cDC1s as compared to cDC2s. While cDC1s from Rab32-deficient mice develop normally and can respond to maturation signals, their capacity to activate CD8 T cells in vivo is impaired. Notably, Rab32- deficient cDC1s retain the ability to stimulate TCR transgenic CD8 T cells ex vivo using both cell-associated antigens and MHC I-binding peptides of varying affinity. However, in vivo, Rab32 is essential for effective CD8 T cell responses to cell-associated antigens, independent of Rab32 expression in T cells themselves. Importantly, Rab32-mediated cross-priming is required for the efficient expansion of tumor-specific CD8 T cells into solid tumors. These findings underscore a critical role for Rab32 in cDC1-mediated cross-priming, highlighting the contribution of non-antigen processing vesicular pathways in shaping CD8 T cell responses to cellular antigens.