MHC CLASS I TYROSINE PHOSPHORYLATION SITE Y320 AUGMENTS CD8+ T CELL PRIMING, EFFECTOR FUNCTION, AND MEMORY RESPONSE

Author

Yimo SunFollow
Gregory A Lizee
Yitao Tang
Priscilla Ortiz
R Eric Davis

Author ORCID Identifier

https://orcid.org/0000-0001-9555-4476

Date of Graduation

5-2025

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Eric Davis

Committee Member

Greg Lizee

Committee Member

Cassian Yee

Committee Member

Stephanie Watowich

Committee Member

Mike Curran

Committee Member

Dan Frigo

Committee Member

Matt Gubin

Abstract

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-2K^b had reduced capacity to generate K^b-restricted cytotoxic T lymphocyte (CTL) responses following viral infection, due (at least in part) to defects in endolysosomal trafficking of H-2K^b 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-2K^b 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.

Keywords

MHC class I, Human Leukocyte Antigen (HLA), cytotoxic T cells, dendritic cells, tyrosine phosphorylation, cytoplasmic tail