Genetic influence on peripheral blood T lymphocyte levels

Abstract

T lymphocytes are a major component of the adaptive immune system. CD4 positive T cell subpopulations regulate B cell and macrophage effector function while CD8 positive T cells are largely responsible for anti-viral cytotoxic activity. The degree of natural variation in the levels and ratios of the various T cell subpopulations is a possible risk factor for the development of autommune disease, infectious disease and cancer. There is some evidence from studies of inbred strains of mice and humans which suggests that variation in T cell subpopulations is genetically influenced. However, family studies alone cannot distinguish between common environmental and shared genetic influences and provide less robust estimates of the heritability than twin studies. To comprehensively examine genetic influences on a selection of important T cell phenotypes, we investigated variation in levels of total lymphocytes, CD3⁺, CD4⁺, CD8⁺, CD3⁺CD4⁺, CD3⁺CD8⁺lymphocytes and in CD4:CD8 ratio as a proportion of lymphocytes and of T cells using the classical twin model approach. Healthy female twin pairs were sampled from the St. Thomas’ UK Adult Twin Registry. A maximum of 103 monozygotic (MZ) and 186 dizygotic (DZ) twins aged 18–80 years participated in the study. Whole blood samples were analysed for T cell subsets by flow cytometry. The relative genetic contribution to these phenotypes was estimated using a variance components model-fitting approach. Heritability estimates were calculated of 65% for CD4:CD8 T cell and lymphocyte ratios, around 50% for absolute lymphocyte, CD3⁺ and CD4⁺ counts, and 56% for CD8⁺ numbers. Unique (rather than shared) familial environment explains the remainder of the variance. Genetic factors have a major influence on the variation in peripheral T cell subset numbers. Polymorphism dictating such variation should be taken into account when assessing risk factors for T cell immune-mediated disease with a genetic background.