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

Mepur H Ravindranath; Narendranath M Ravindranath; Senthamil R Selvan; Edward J Filippone; Carly J Amato-Menker; Fatiha El Hilali

doi:10.3390/vaccines10020339

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

Vaccines (Basel). 2022 Feb 21;10(2):339. doi: 10.3390/vaccines10020339.

Authors

Mepur H Ravindranath^{1

2}, Narendranath M Ravindranath³, Senthamil R Selvan⁴, Edward J Filippone⁵, Carly J Amato-Menker⁶, Fatiha El Hilali⁷

Affiliations

¹ Department of Hematology and Oncology, Children's Hospital, Los Angeles, CA 90027, USA.
² Emeritus Research Scientist at Terasaki Foundation Laboratory, Santa Monica, CA 90064, USA.
³ Norris Dental Science Center, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Tetracore Inc., Rockville, MD 20850, USA.
⁵ Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19145, USA.
⁶ Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.
⁷ The Faculty of Medicine and Pharmacy of Laayoune, Ibn Zohr University, Agadir 70000, Morocco.

Abstract

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.

Keywords: Face 1; Face 2; Face 3; Face 4; HLA; heavy chain; heterodimers; homodimers; monoclonal antibodies; monomeric; α1 and α2 helices; β2microglobulin.

Publication types

Review