Abstract
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 α1/α2 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.
Highlights
HLA class I molecules are expressed on almost all nucleated cells and play a key role in the immune responses to pathogens, cancer cells, and autoantigens
Our aim was to correlate the immunogenicity of HLA-C MM with HLA-C mRNA expression levels, with disparities in aas known to be relevant for peptide binding and/or T cell receptor (TCR) recognition, and with concomitant HLA-DPB1 incompatibilities
By quantifiying CD137+CD8+CD56− T lymphocytes at day 14, we focused on T cell but not NK cell-mediated alloreactivity
Summary
HLA class I molecules are expressed on almost all nucleated cells and play a key role in the immune responses to pathogens, cancer cells, and autoantigens In addition to their extremely high level of allelic polymorphism, they are characterized by variable levels of expression potentially influencing their function. Several studies have recently reported variability in the expression of different HLA-C serotypes, as determined at the cell surface or mRNA steady-state levels [5,6,7,8]. The C*14:02 allotype, reportedly classified as high if not the highest [5] expression allele, is characterized by the 263ins variant associated with low expression [8] The correlation of these genetic markers with expression levels has been challenged by a few other studies [6, 10, 11]. By using group-specific polymerase chain reaction (PCR), individuals expressing the same HLA-C allele did show variability in mRNA steady-state amounts within a given serotype that could possibly be correlated with specific haplotypes [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
