A genetic basis for IFN-gamma production and T-bet expression in humans.

Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-gamma and TNF-alpha with heritabilities of 0.85 (95% confidence intervals, 0.74-0.95) and 0.72 (0.50-0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-gamma production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-kappaB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84-1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.