Impaired development of human Th1 cells in patients with deficient expression of STAT4.

IL-12 activates STAT4, which is a critical regulator of inflammation and T helper type I (Th1) lineage development in murine systems. The requirement for STAT4 in the generation of human Th1 cells has not been examined thoroughly. Compared with control Th1 cultures, expression of the Th1 genes IFNgamma, IL-12Rbeta2, and TNFalpha is greatly reduced in Th1 cultures of CD4 T cells isolated from lymphoma patients after autologous stem cell transplantation who have acquired STAT4 deficiency. Moreover, IL-4 and IL-5 production is increased in patient Th1 cultures though there are no defects in the development of Th2 cells. Reconstitution of STAT4 in patient T cells allowed recovery of IFNgamma and IL-12Rbeta2 expression, whereas ectopic expression of IL-12Rbeta2 did not rescue STAT4 expression, and increased IFNgamma production only to levels intermediate between control and patient samples. These results demonstrate that, as in murine systems, STAT4 is required for optimal human Th1 lineage development.