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

Area of Science:

• Immunology
• Transplantation immunology

Background:

• Direct alloresponse is crucial in transplant rejection, involving recipient T cells recognizing intact peptide-major histocompatibility complex (pMHC) complexes.
• Understanding alloreactive CD8+ T cells, their frequency, and specificity against individual human leukocyte antigen (HLA) alleles is limited.

Purpose of the Study:

• To determine the precursor frequency and specificity of alloreactive CD8+ T cells against single HLA alleles.
• To identify immunogenic kidney-specific peptides recognized by anti-HLA-A*02:01 T cells.

Main Methods:

• Utilized K562 cell-based artificial antigen-presenting cells (aAPCs) engineered to express specific HLA alleles (HLA-A*01:01, HLA-A*02:01, HLA-A*03:01).
• Developed peptide-exchangeable aAPCs for HLA-A*02:01 to test peptide specificity.
• Analyzed T cell proliferation, interferon-gamma secretion, and cytolytic activity.

Main Results:

• Precursor frequency of alloreactive CD8+ T cells against a single HLA allele ranged from 0.1% to 0.5%.
• Alloreactive T cells demonstrated significant HLA specificity with limited crossreactivity.
• Identified two immunogenic kidney-derived peptides presented by HLA-A*02:01 recognized by T cells from multiple donors.

Conclusions:

• Established the precursor frequency and MHC specificity of direct alloreactive CD8+ T cells.
• Developed a novel toolkit for studying alloresponses and identifying specific peptide targets.
• Findings enhance understanding of transplant rejection mechanisms and enable patient monitoring.