Introduction to HLA

The human leukocyte antigen (HLA) is a cluster of related glycoproteins encoded by the major histocompatibility complex (MHC) gene complex, which is named for their location on the cell membrane of leukocytes in humans. HLA is also termed as human MHC, which is mainly divided into HLA class I, and HLA class II. HLA class I proteins consist of a polymorphic α chain and a monomorphic β-globulin chain that widely distributes on most nucleated cells form functional receptors, including major MHC class I (HLA-A, HLA-B, and HLA-C) and minor class I (HLA-E, HLA-F, and HLA-G). Whereas, HLA class II proteins consist of two polymorphic chains (α chain and β chain) that are primary expressed by antigen-presenting cells, B cells, and T cells, including major MHC class II (HLA-DP, HLA-DQ, and HLA-DR) and minor class II (HLA-DM, and HLA-DO).

Genetic organization of the HLA complex and structure of HLA class I and II molecules. Fig.1 Genetic organization of the HLA complex and structure of HLA class I and II molecules. (Klein, 2000)

HLA recognizes and processes foreign peptides and regulates humoral or cellular immune responses, serving as a powerful arm in human adaptive and innate immunity. And HLA antigens act as a key factor in immune-related pathways and diseases, especially in transfusion and transplantation, autoimmunity, infectious diseases, and even cancers, which also play important roles in immunotherapies development, particularly for cancer treatment by T cell immunotherapy.

γδ T Cell Activated by HLA

B lymphocytes and T lymphocytes are two major components of the human adaptive immune, which mediate the humoral response and cellular immune response, respectively. T lymphocytes are categorized into αβ T cells and γδ T cells according to the expression of their respective T cell receptor (TCR), of which γδ T cells are a small proportion of T lymphocytes with featured γδ-TCRs playing important actions in innate and adaptive immunity. They recognize a spectrum of ligands or antigens, participating in anti-infections, inflammatory reactions, immune memory, tumor immune surveillance, and so forth.

Similar to the conventional and majority T cells, namely αβ T cells, these unconventional γδ T cells are capable to recognize MHC molecules. In humans, several HLA antigens have been identified that could react with and activate γδ T cells. In 1989, an alloreactive γδ T cell clone has been demonstrated by Ciccone et al. that recognized and targeted a polymorphic determinant of HLA class I molecule (HLA-24), even efficiently lysed HLA-24-transfected cells. Lately, Spits et al. have reported that cytotoxic γδ T cells clones could be activated by HLA-A2 and its mutants, secreting cytotoxic and effector molecules, such as interleukin 2, interferon-γ, and granulocyte-macrophage colony-stimulating factor. Afterward, γδ TCR clones have been shown that also recognized other HLA molecules, like HLA-B27 and HLA-A∗24:02. All these HLA recognition identification provided reference or clues for the transplantation improvement and cancer immunotherapy by engineered γδ T cells.


  1. Klein, J., Sato, A. The HLA system. New England Journal of Medicine. 2000, 343(10): 702-709.
  2. Ciccone, E., et al. Specificity of human T lymphocytes expressing a γ/δ T cell antigen receptor. Recognition of a polymorphic determinant of HLA class I molecules by a γ/δ clone. European Journal of Immunology. 1989, 19(7): 1267-1271.
  3. Spits, H. et alCytotoxic activity and lymphokine production of T cell receptor (TCR)-alpha beta+ and TCR-gamma delta+ cytotoxic T lymphocyte (CTL) clones recognizing HLA-A2 and HLA-A2 mutants. Recognition of TCR-gamma delta+ CTL clones is affected by mutations at positions 152 and 156. Journal of Immunology. 1990, 144(11): 4156-4162.
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