Abstract
Within an individual, six different HLA class II heterodimers are expressed co-dominantly by two alleles of HLA-DR, -DQ, and -DP loci. However, it remained unclear which HLA allotypes were used in T cell responses to a given antigen. For the measurement of the CD4+ T cell responses restricted by a single HLA allotype, we established a panel of artificial antigen-presenting cells (aAPCs) expressing each single HLA allele of 20 HLA-DRB1, 16 HLA-DQ, and 13 HLA-DP alleles. CD4+ T cell responses to cytomegalovirus (CMV) pp65 restricted by single HLA class II allotype defined in 45 healthy donors. The average magnitude of CD4+ T cell responses by HLA-DR allotypes was higher than HLA-DQ and HLA-DP allotypes. CD4+ T cell responses by DRA*01:01/DRB1*04:06, DQA1*01:02/DQB1*06:02, DPA1*02:02/DPB1*05:01 were higher among the other alleles in each HLA-DR, -DQ, and -DP locus. Interestingly, the frequencies of HLA-DR alleles and the positivity of specific allotypes showed an inverse correlation. One allotype within individuals is dominantly used in CD4+ T cell response in 49% of donors, and two allotypes showed that in 7% of donors, and any positive response was detected in 44% of donors. Even if one individual had several dominant alleles, CD4+ T cell responses tended to be restricted by only one of them. Furthermore, CD8+ and CD4+ T cell responses by HLA class I and class II were correlated. Our results demonstrate that the CD4+ T cell preferentially use a few dominant HLA class II allotypes within individuals, similar to CD8+ T cell response to CMV pp65.
Highlights
The diversity of human leucocyte antigen (HLA) molecules is generated by mutations, driven and maintained by purifying selection or balancing selection, such as negative frequency-dependent selection or heterozygote advantage [1,2,3,4,5]
To measure single HLA allotype-restricted CD4+ T cell response, K562 cell line expressing CD80, CD83, and CD137L was transduced with single HLA-DR, -DQ, or -DP allele (Figure 1A)
The artificial antigen-presenting cells (aAPCs) expressing 20 HLA-DR alleles, 16 HLA-DQ alleles, or 13 HLA-DP alleles were established to cover the common alleles, which are at frequencies above 1% in Koreans
Summary
The diversity of human leucocyte antigen (HLA) molecules is generated by mutations, driven and maintained by purifying selection or balancing selection, such as negative frequency-dependent selection or heterozygote advantage [1,2,3,4,5]. High allelic diversity in a population is likely to maximize the probability of survival for some individuals with protective HLA alleles against a pathogen [6,7,8,9]. The association between HLA alleles and infectious disease was studied by comparing the allele frequencies of patients with a normal population [10,11,12]. Classical MHC class I and II molecules are encoded by HLA-A, -B, and -C loci and by HLA-DR, -DQ, and -DP loci, respectively [14, 15]. All the HLA molecules can present peptide antigen to CD8+ or CD4+ T cells, but it was not well defined whether each of these HLA allotypes is dominantly used for T cell responses to a particular antigen within individuals
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