Involvement of the Major Histocompatibility Complex region in the genetic regulation of circulating CD8⁺ T‐cell numbers in humans

Abstract

Variability in T-lymphocyte numbers is partially explained by a genetic regulation. From studies in animal models, it is known that the Major Histocompatibility Complex (MHC) is involved in this regulation. In humans, this has not been shown yet. The objective of the present study was to test the hypothesis that genes in the MHC region influence the regulation of T-lymphocyte numbers. Two approaches were used. Association studies between T-cell counts (CD4(+) and CD8(+)) or total lymphocyte counts and HLA class I alleles (A and B) or mutations in the HFE (C282Y and H63D), the hemochromatosis gene, in an unrelated population (n = 264). A second approach was a sibpair correlation analysis of the same T-cell counts in relation to HLA-HFE haplotypes in subjects belonging to 48 hemochromatosis families (n = 456 sibpairs). In the normal population, results showed a strong statistically significant association of the HLA-A*01 with high numbers of CD8(+) T cells and a less powerful association with the HLA-A*24 with low numbers of CD8(+) T cells. Sibpair correlations revealed the most significant correlation for CD8(+) T-cell numbers for sibpairs with HLA-HFE-identical haplotypes. This was not observed for CD4(+) T cells. These results show that the MHC region is involved in the genetic regulation of CD8(+) T-cell numbers in humans. Identification of genes responsible for this control may have important biological and clinical implications.

Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8+ T lymphocyte numbers

“…There is growing evidence, both in human and animal models, that the numbers of lymphocytes are genetically determined [28,35 -41]. Recent work has shown that the MHC class I genetic region is involved in this regulation [28]. Other nutritional but at present unidentified factors may be involved that might contribute to the persistent failure to observe any correlation between lymphocyte numbers and iron stores in homozygous female patients.…”

“…Surprisingly, no correlation between serum Trf levels and CD4 + or total lymphocyte numbers was seen. Such a result brings to light once more the involvement of MHC class I in this disorder [10,28,33]. CD8 + but not CD4 + T lymphocytes are activated and proliferate in the context of MHC class I molecules (reviewed in [17]).…”

“…Clinical and laboratory data from the present study population have been previously published [4,9,13,28].…”

“…This healthy population included 181 males (mean age 40 T 15) and 245 females (mean age 44 T 15). All subjects had been previously HFE genotyped as described before [28]. Exclusion criteria for the healthy population study were age <20 years old and evidence of viral infection (HBV, HCV, HTLV, HIV1 and HIV2).…”

Human Leukocyte Antigens I and II Haplotypes Associated With Human Papillomavirus 16-Positive Invasive Cervical Cancer in Mexican Women

“…In this study, the authors reported a higher frequency of HLA-A1 in the group of subjects with high CD+ T-cell counts (0.168 vs 0.089; P = 0.003). 26 Identification of real primary or secondary disease gene is complicated by the strong linkage disequilibrium that exists among HLA complex genes and by environmental factors such as specific HPV infection and CC. For example, some studies have reported positive association with B7, 12,16 which is in linkage disequilibrium with DRB1*1501-DQB1*0602, a haplotype also identified with increased risk for CC.…”