Mutation of Conserved Mhc Class I Cytoplasmic Tyrosine Affects CD8+ T Cell Priming, Effector Function, and Memory Response

Authors

Yimo Sun
Yitao Tang
Priscilla Ortiz
Barbara Nassif Rausseo
Barbara Pazdrak
Lama Elzohary
Arjun Katailiha
Amjad Talukder
Cassian Yee
Richard Eric Davis
Gregory Lizée

Language

English

Publication Date

1-1-2025

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2025.1572342

PMID

41098740

PMCID

PMC12518231

PubMedCentral® Posted Date

9-30-2025

PubMedCentral® Full Text Version

Post-print

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-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.

Keywords

Animals, Humans, Mice, Immunologic Memory, Mutation, CD8-Positive T-Lymphocytes, Tyrosine, Dendritic Cells, Lymphocyte Activation, HLA-A2 Antigen, Histocompatibility Antigens Class I, Antigen Presentation, MHC class I, human leukocyte antigen (HLA), cytotoxic T cells, dendritic cells, tyrosine phosphorylation, cytoplasmic tail

Published Open-Access

yes

Recommended Citation

Sun, Yimo; Tang, Yitao; Ortiz, Priscilla; et al., "Mutation of Conserved Mhc Class I Cytoplasmic Tyrosine Affects CD8+ T Cell Priming, Effector Function, and Memory Response" (2025). Faculty, Staff and Student Publications. 5527.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5527