Allorecognition of HLA C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide Binding Region Residues, HLA C Expression, and HLA DPB1 Disparities
HLA C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA C incompatibilities. To get better insight into presumably permissive HLA C MMs, we have developed a one way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56 CD137+CD8+ lymphocytes in HLA C incompatible combinations. T cell mediated alloresponses were correlated with genetic markers such as HLA C mRNA expression and the number of amino acid (aa) MMs in the a1/a2 domains (peptide binding region) Because of the high rate of HLA DPB1 incompatibilities in HLA A B C DRB1 and DQB1 matched unrelated HSCT patient/donor pairs, the impact of HLA DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA C mismatched pairs with a positive assay in 52% of the combinations (2.3 18.6% activated CTLs) representing 24 different HLA A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA C alleles. The HLA C*03:03/03:04 MM did not induce any positive alloresponse in five MLRs. We also identified HLA C*02:02 and HLA C*06:02 as mismatched alleles with lower immunogenicity, and HLA C*14:02 as a more immunogenic MM. A difference of at least 10 aa residues known to impact peptide/T cell receptor (TCR) binding and a bystander HLA DPB1 incompatibility had a significant impact on CTL alloreactivity (p 0.021) The same HLA C MM, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T cell repertoire of responding cells. In conclusion, mismatched HLA C alleles differing by 10 or more aas in the peptide/TCR binding region, when occurring together with HLA DPB1 incompatibilities, should be considered as high risk MMs in unrelated HSCT.
Front. Immunol.