Four Faces of Cell-Surface HLA Class-I: Their Antigenic and Immunogenic Divergence Generating Novel Targets for Vaccines

• Published in: Vaccines (Basel) 2022-02, Vol.10 (2), p.339
• Main Authors: Ravindranath, Mepur H, Ravindranath, Narendranath M, Selvan, Senthamil R, Filippone, Edward J, Amato-Menker, Carly J, El Hilali, Fatiha
• Format: Article
• Language: English
• Subjects: Alleles; Amino acid composition; Amino acids; Antibodies; Antigen presentation; Antigens; Bladder cancer; Carbohydrates; CD8 antigen; Cell surface; Chains; Chemokines; Cysteine; Cytokines; Cytotoxicity; Dimerization; Divergence; Epitopes; Epstein-Barr virus; Exposure; Genes; heavy chain; Helices; Histocompatibility antigen HLA; HLA; homodimers; Immunogenicity; Immunotherapy; Infections; Inflammation; Isoforms; Leukocytes; Lymphocytes; Lymphocytes T; Malignancy; Monoclonal antibodies; monomeric; Peptides; Polymorphism; Polypeptides; Post-translation; Proteins; Review; Translation; Transplantation; Vaccines; Viral infections; α1 and α2 helices; β2 Microglobulin; β2microglobulin
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines10020339

Leukocyte cell-surface HLA-I molecules, involved in antigen presentation of peptides to CD8+ T-cells, consist of a heavy chain (HC) non-covalently linked to β2-microglobulin (β2m) (Face-1). The HC amino acid composition varies across all six isoforms of HLA-I, while that of β2m remains the same. Each HLA-allele differs in one or more amino acid sequences on the HC α1 and α2 helices, while several sequences among the three helices are conserved. HCs without β2m (Face-2) are also observed on human cells activated by malignancy, viral transformation, and cytokine or chemokine-mediated inflammation. In the absence of β2m, the monomeric Face-2 exposes immunogenic cryptic sequences on these cells as confirmed by HLA-I monoclonal antibodies (LA45, L31, TFL-006, and TFL-007). Furthermore, such exposure enables dimerization between two Face-2 molecules by SH-linkage, salt linkage, H-bonding, and van der Waal forces. In HLA-B27, the linkage between two heavy chains with cysteines at position of 67 of the amino acid residues was documented. Similarly, several alleles of HLA-A, B, C, E, F and G express cysteine at 67, 101, and 164, and additionally, HLA-G expresses cysteine at position 42. Thus, the monomeric HC (Face-2) can dimerize with another HC of its own allele, as homodimers (Face-3), or with a different HC-allele, as heterodimers (Face-4). The presence of Face-4 is well documented in HLA-F. The post-translational HLA-variants devoid of β2m may expose several cryptic linear and non-linear conformationally altered sequences to generate novel epitopes. The objective of this review, while unequivocally confirming the post-translational variants of HLA-I, is to highlight the scientific and clinical importance of the four faces of HLA and to prompt further research to elucidate their functions and their interaction with non-HLA molecules during inflammation, infection, malignancy and transplantation. Indeed, these HLA faces may constitute novel targets for passive and active specific immunotherapy and vaccines.