Submitted September 17, 2008
Accepted March 30, 2009
Impaired development of human Th1 cells in patients with deficient expression of STAT4
Hua-Chen Chang*, Ling Han, Ritobrata Goswami, Evelyn T. Nguyen, David Pelloso, Michael J. Robertson, and Mark H. Kaplan
Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
Bone Marrow and Stem Cell Transplantation Program, Lymphoma Program, and the Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
* Corresponding author; email: huchang{at}iupui.edu.
IL-12 activates STAT4, which is a critical regulator of inflammation and Th1 lineage development in murine systems. The requirement for STAT4 in the generation of human Th1 cells has not been examined thoroughly. Compared to control Th1 cultures, expression of the Th1 genes IFN
, IL-12R
2 and TNF
is greatly reduced in Th1 cultures of CD4 T cells isolated from lymphoma patients following autologous stem cell transplant that 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 and IL-12R2 expression, while ectopic expression of IL-12R2 did not rescue STAT4 expression, and increased IFN 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.
