MUTATION OF CONSERVED MHC CLASS I CYTOPLASMIC TYROSINE AFFECTS CD8+ T CELL PRIMING, EFFECTOR FUNCTION, AND MEMORY RESPONSE

Yimo Sun^1,2Yitao Tang²Priscilla Ortiz¹Barbara Nassif Rausseo²Barbara Pazdrak¹Lama Elzohary¹ARJUN KATAILIHA¹Amjad H Talukder¹Cassian Yee¹Richard Eric Davis^1*Gregory Lizee^1*

• ¹University of Texas MD Anderson Cancer Center, Houston, United States
• ²Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas, United States

The cytoplasmic domain of MHC class I (MHC-I) molecules contains a single, highly conserved tyrosine residue (Y320). In previous work, we found that mice expressing a Y320F-mutated form of H-2Kb had reduced capacity to generate Kb-restricted cytotoxic T lymphocyte (CTL) responses following viral infection, due at least in part to defects in endolysosomal trafficking of H-2Kb and antigen cross-presentation by dendritic cells (DCs). In this study, we investigated whether there are additional, post-presentation dependencies on Y320 for T cell priming. We engineered both human-and mouse-derived antigen-presenting cells (APCs) to express either wild-type MHC-I or variants of MHC-I containing Y320F or Y320E mutations. We found that Y320E-mutated HLA-A*0201 elicited enhanced in vitro priming and expansion of human antigen-specific CD8+ T cells, which showed a unique transcriptional profile compared to T cells primed with APCs expressing either WT or Y320F-mutated A*0201. Furthermore, the Y320E variant of H-2Kb expressed in the context of a murine DC vaccine model induced altered T cell differentiation kinetics while improving both anti-tumor immunity and augmenting the magnitude of memory CD8+ T cell responses in vivo. These results suggest that Y320 phosphorylation of MHC-I may play a role in determining the fate and function of CD8+ T cells and suggest a novel strategy for improving DC-based cancer immunotherapies.