MHC Class I Tyrosine Phosphorylation Site Y320 Augments CD8+ T Cell Priming, Effector Function, and Memory Response

<p>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 <em>in vitro</em> 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 <em>in vivo</em>. 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Sun, Yimo
• Lizee, Gregory A
• Tang, Yitao
• Ortiz, Priscilla
• Eric Davis, R
• <p>https://orcid.org/0000-0001-9555-4476</p>

Contributors dc:contributor

• Eric Davis
• Greg Lizee
• Cassian Yee

• MHC class I
• Human Leukocyte Antigen (HLA)
• cytotoxic T cells
• dendritic cells
• tyrosine phosphorylation
• cytoplasmic tail
• Immunity
• Immunotherapy
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1452

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2509