Non-Classical HLA-E and what we know to date

The non-classical major histocompatibility complex (MHC) class I molecules is one of the emerging fields being studied in the last decade. The non-classical class Ib (HLA-Ib) molecules include HLA-E, HLA-F, HLA-G, and HLA-H. These non-classical HLA-Ib molecules, including HLA-E, have a more restricted polymorphism pattern, in comparison to the classical HLA molecules (HLA-Ia). The main role of HLA-E in the body is for immune surveillance, as it has been shown that it can present self-peptides originating from the leader sequence of the other HLA molecules, which signal to the immune system that the cell is healthy (1). Its restricted polymorphism and its involvement in both innate and adaptive immunity has made HLA-E an extensively studied MHC class Ib antigen in recent years.

HLA-E can exhibit a minimal polymorphism with only two non-synonymous functional HLA-E alleles, HLA-E*01:01 and HLA-E*01:03. HLA-E*01:03 differs from HLA-E*01:01 by a single amino acid substitution (gly to arg) at position 107 of the α2 heavy chain domain (2). Although the two alleles appear to be evenly distributed in the human population (approximately 50% each), they differ with respect to their quantitative cell surface expression. HLA-E*01:03 is expressed at higher concentration on transfected cells compared to HLA-E*01:01 (3). In hematopoietic stem cell transplantation (HSCT), HLA-E*01:03 homozygosity was associated with a lower risk of Graft Versus Host Disease (GVHD), decreased mortality and a higher disease-free survival rate, whereas HLA-E*01:01 homozygosity was associated with an increased risk of bacterial infection (4). As of March of 2021, 271 alleles, 110 proteins, and 7 null alleles have been identified and included in the IPD-IMGT/HLA Database (release v3.44.0).

 Since HLA-E is expressed by myeloid dendritic cells, B cells, natural killer (NK) cells, T cells, and is highly expressed in neutrophils, it plays an important role in immune response (5). It regulates NK cell function and is the only known ligand for the C-type lectin receptor CD94 combined with different NKG2 subunits expressed on NK and CD8+ αβ T cells (6). Recent evidence supports the role of HLA-E in presentation of peptides to the αβ TCR expressed on CD8+ T cells, like the classical HLA-Ia molecules. HLA-E can also present microbial-derived peptides from human viruses or bacteria, thereby inducing T-cell responses. These diverse roles highlight the importance of HLA-E molecules as restriction elements for the specific T-cell responses against pathogens such as CMV, Epstein–Barr virus (EBV) or mycobacteria (Mycobacterium tuberculosis) (8-9).

 There have been ongoing studies looking at the effect of donor and patient HLA-E characteristics on the outcome of HSCT. Some of the results have been inconclusive, but a recent study containing the largest data set to date from the Center for International Blood and Marrow Transplant Research (CIBMTR) showed an association between donor HLA-E*01:03 homozygous genotype, disease-free survival, and transplant rate mortality in a T cell replete transplantation setting (10). This association has been reported in two different studies  to date (7). With this and the readily improved sequencing technology, DKMS, one of the largest stem cell donor registries in the world, carried out a population genetic study where more than 2.5 million potential hematopoietic stem cell donors of 104 populations were genotyped for HLA-E by NGS (11). The studies confirmed the known dominance of alleles HLA-E*01:01 and HLAE*01:03. HLA-E*01:01 is more frequent in Africa and the western part of South America, while HLA-E*01:03 is more prevalent in Southeast and East Asia (11). The data presented in these studies may be helpful for the basis of further population genetics studies and for optimizing stem cell donor searches as we continue to learn more about the associations of HLA-E and its clinical implications.

 Discussions have suggested that targeting HLA-Ib genes, particularly HLA-E, may be an option for developing globally effective therapies and vaccines. The monomorphic diversity of these genes would facilitate the development of CD8+ T-cell mediated vaccines that would be applicable across global populations (1). Despite the emerging evidence identified to date, there are still some important gaps in our knowledge regarding the role of HLA-E in immunity. As the technologies and methodologies are continuously improving this will allow us to increase our knowledge on HLA-E and improve clinical outcomes for patients.




  1. E.J. Grant, A.T. Nguyen, C.A. Lobos, C. Szeto, D.S.M. Chatzileontiadou, S. Gras, The unconventional role of HLA-E: the road less traveled, Mol. Immunol. 120 (2020) 101–112.
  2. Iwaszko M., Bogunia-Kubik K., The role of HLA-E polymorphism in immunological response., Postepy Hig Med Dosw. 2011; 65 ([in Polish]): 616-626
  3. Charron, D., & Petersdorf, E. (2013). The HLA system in hematopoietic stem cell transplantation. Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation, 19–38. doi:10.1016/b978-0-12-416004-0.00002-1 
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  5. Boegel, S., Lower, M., Bukur, T., Sorn, P., Castle, J.C., Sahin, U., 2018. HLA and pro- teasome expression body map. BMC Med. Genomics 11, 36.
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  7. C. Tsamadou, D. FuÃàrst, T. Wang, N. He, S.J. Lee, S.R. Spellman, K. Fleischhauer, K. C. Hsu, S. Paczesny, M.R. Verneris, H. Schrezenmeier, J. Mytilineos, Donor HLA- E status associates with disease-free survival and transplant-related mortality after non in vivo T cell-depleted HSCT for acute leukemia, Biol. Blood Marrow Transplant. 25 (12) (2019) 2357-2365, bbmt.2019.08.007.
  1. Heinzel AS, Grotzke JE, Lines RA, Lewinsohn DA, McNabb AL, Streblow DN, et al. HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J Exp Med 2002;196:1473-81.
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  3. C. Tsamadou, D. Fürst, T. Wang, N. He, S.J. Lee, S.R. Spellman, K. Fleischhauer, K. C. Hsu, S. Paczesny, M.R. Verneris, H. Schrezenmeier, J. Mytilineos, Donor HLA- E status associates with disease-free survival and transplant-related mortality after non in vivo T cell-depleted HSCT for acute leukemia, Biol. Blood Marrow Transplant. 25 (12) (2019) 2357–2365.
  4. Sauter J, Putke K, Schefzyk D, et al. HLA-E typing of more than 2.5 million potential hematopoietic stem cell donors: methods and population-specific allele frequencies. Human Immunol. 2020.