Abstract
To define whether individual human leukocyte antigen (HLA) class I allotypes are used preferentially in human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte responses, CD8+ T cell responses restricted by up to six HLA class I allotypes in an individual were measured in parallel using K562-based artificial antigen-presenting cells expressing both CMV pp65 antigen and one of 32 HLA class I allotypes (7 HLA-A, 14 HLA-B, and 11 HLA-C) present in 50 healthy Korean donors. The CD8+ T cell responses to pp65 in the HLA-C allotypes were lower than responses to those in HLA-A and -B allotypes and there was no difference between the HLA-A and HLA-B loci. HLA-A*02:01, -B*07:02, and -C*08:01 showed the highest magnitude and frequency of immune responses to pp65 at each HLA class I locus. However, HLA-A*02:07, -B*59:01, -B*58:01, -B*15:11, -C*03:02, and -C*02:02 did not show any immune responses. Although each individual has up to six different HLA allotypes, 46% of the donors showed one allotype, 24% showed two allotypes, and 2% showed three allotypes that responded to pp65. Interestingly, the frequencies of HLA-A alleles were significantly correlated with the positivity of specific allotypes. Our results demonstrate that specific HLA class I allotypes are preferentially used in the CD8+ T cell immune response to pp65 and that a hierarchy among HLA class I allotypes is present in an individual.
Highlights
The fraction of a population infected with cytomegalovirus (CMV) depends on the socioeconomic status of the population
To determine whether individual Human leukocyte antigen (HLA) class I allotypes are used preferentially or in human virus-specific cytotoxic T lymphocytes (CTLs) responses, we established a platform for measuring the CD8+ T cell response by presenting the pp65 peptide intrinsically to various HLA allotypes using K562-based artificial antigen-presenting cell (aAPC) (Figure 1)
The coverage of 32 HLA class I allotypes (7 Human leukocyte antigen class I (HLA-A), 14 HLA-B, and 11 HLA-C) observed in 50 healthy Korean donors was 85.82% for the HLA-A locus, 75.69% for the HLA-B locus, and 83.04% for the HLA-C locus in the Korean population analyzed in our laboratory data from over 10,000 donors
Summary
The fraction of a population infected with cytomegalovirus (CMV) depends on the socioeconomic status of the population. After primary infection, which frequently occurs during early childhood [1], CMV establishes lifelong latency under control of the immune system. Human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTLs) are involved in the early immune response and are important defense mechanism in CMV infections [3]. Protection from CMV disease in immune-compromised hosts has been correlated with recovery of host virus-specific CD8+ T cell responses [6]. Protective immunity can be successfully transferred by infusion of donor-derived CMV-specific CD8+ CTL clones [7, 8]. Assessment of clonal diversity of T cell responses against human CMV, a major cause of morbidity in immune-depressed patients, provides important insights into the molecular basis of T cell immunodominance and has clinical implications for immune monitoring and immunotherapy of CMV infections [9]
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