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 IFN gamma, IL-12R beta 2, and TNF alpha 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 IFN gamma and IL-12R beta 2 expression, whereas ectopic expression of IL-12R beta 2 did not rescue STAT4 expression, and increased IFN gamma 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. (Blood. 2009; 113: 5887-5890)