Major histocompatibility complex and peptide specificity underpin CD8+ T cell direct alloresponse

Weiwen Zhang; Fernanda M Roversi; Anna B Morris; Kristina Ortiz; Grace Zhou; Annette Hadley; Xueqiong Zhang; Juliete A F Silva; Cynthia P Breeden; Zhuldyz Zhanzak; Haydn T Kissick; Christian P Larsen

doi:10.1016/j.ajt.2024.10.011

Major histocompatibility complex and peptide specificity underpin CD8⁺ T cell direct alloresponse

Am J Transplant. 2024 Oct 20:S1600-6135(24)00640-3. doi: 10.1016/j.ajt.2024.10.011. Online ahead of print.

Affiliations

¹ Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA.
² Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
³ Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
⁴ Winship Cancer Institute of Emory University, Atlanta, Georgia, USA; Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA; Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. Electronic address: haydn.kissick@emory.edu.
⁵ Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA; Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA; Winship Cancer Institute of Emory University, Atlanta, Georgia, USA. Electronic address: clarsen@emory.edu.

PMID: 39433089
DOI: 10.1016/j.ajt.2024.10.011

Abstract

The direct alloresponse, pivotal in transplant rejection, occurs when recipient T cells recognize intact allogeneic peptide-major histocompatibility complex (pMHC) complexes. Despite extensive research, our understanding of alloreactive CD8⁺ T cells against an individual MHC allele in humans remains limited, especially their precursor frequency, MHC specificity, and peptide specificity. By using K562 cell-based artificial antigen-presenting cells expressing human leukocyte antigen (HLA)-A∗01:01, HLA-A∗02:01, or HLA-A∗03:01, we determined that the precursor frequency of alloreactive CD8⁺ T cells against a single MHC allele ranges from 0.1% to 0.5%. Further, these cells exhibited MHC specificity regarding proliferation, activation, interferon gamma secretion, and cytolytic ability, with limited crossreactivity toward nontargeted MHC alleles. Focusing on anti-A2 alloreactive CD8⁺ T cells, we developed a peptide-exchangeable artificial antigen-presenting cell that displays selected peptides on HLA-A∗02:01. From a set of 95 computationally curated A2-restricted peptides most abundant in renal tubular cells, we identified 2 immunogenic kidney peptides across multiple donors. Overall, our findings significantly enhance the understanding of direct alloresponse and provide a toolkit for future mechanistic studies and reproducible patient monitoring.

Keywords: CD8(+) T cells; alloantigen; crossreactivity; direct allorecognition; precursor frequency; specificity.