HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation

Haematologica. 2024 Apr 1;109(4):1121-1127. doi: 10.3324/haematol.2023.283812.

Abstract

The null allele HLA-C*04:09N differs from HLA-C*04:01 in a frameshift mutation within its cytoplasmic domain, resulting in translation of 32 additional amino acids that are assumed to prevent cell surface expression. However, we recently identified a multiple myeloma-reactive T-cell receptor (TCR) that appeared to recognize antigen presented on HLA-C*04:09N and encouraged us to ask whether HLA-C*04:09N, albeit not easily detectable at the cell surface, can present antigen sufficient for T-cell activation. We generated two HLA-class I-deficient cell lines, re-expressed HLAC* 04:09N, detected HLA expression by flow cytometry, and tested for T-cell activation using a cytomegalovirus peptide- specific HLA-C*04:01-restricted TCR. In both cell lines, HLA-C*04:09N expression was detectable at the cell surface and could be enhanced by IFN-γ exposure. Recombinant HLA-C*04:09N expression was sufficient for T-cell activation in vitro, which could be blocked by an HLA-class I-specific antibody, suggesting HLA-TCR interaction at the cell surface. Peripheral blood mononuclear cells isolated from an individual who physiologically expressed HLA-C*04:09N triggered peptide-specific T-cell activation, confirming our results with cells with natural HLA expression levels. In conclusion, we present peptide-specific HLA-C*04:09N-restricted T-cell activation and suggest consideration of this allele in the appropriate clinical context, such as allogeneic stem cell transplantation, or in the setting of cellular therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HLA-C Antigens* / genetics
  • Humans
  • Leukocytes, Mononuclear*
  • Peptides
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes, Cytotoxic

Substances

  • HLA-C Antigens
  • Peptides
  • Receptors, Antigen, T-Cell

Grants and funding

Funding: This work was supported by Deutsche Krebshilfe e.V. (70113355; to LH), Berliner Krebsgesellschaft e.V. (HAFF202013 MM; to LH), the German Cancer Consortium (DKTK; to LH), and the European Union (ERC Advanced Grant Neo-T, 882963; toTB).