Jak3 negatively regulates dendritic-cell cytokine production and survival

Cytokines are critical in regulating the development and function of diverse cells. Janus kinase 3 (JAK3) is a tyrosine kinase expressed in hematopoietic cells that associates with the common gamma chain (gammac) and is required for signaling for a family of cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21; deficiency of either JAK3 or gammac results in severe combined immunodeficiency (SCID). While JAK3 is essential for lymphoid-cell development, the potential roles for JAK3 in regulating dendritic cells (DCs) were unclear. Herein, we show that although CD8+CD11c+ splenic DCs are absent in Jak3-/- mice, bone marrow-derived DCs developed normally in vitro from Jak3-/- precursor cells. In fact, the survival of Jak3-/- DCs was enhanced, and they expressed lower levels of proapoptotic proteins. Jak3-/- DCs exhibited normal antigen uptake and up-regulation of costimulatory molecules. However, Jak3-/- DCs produced more IL-12 and IL-10 in response to Toll-like Receptor ligands, which correlated with enhanced T helper 1 (Th1) differentiation in vivo. In summary, JAK3 is not essential for DC development but unexpectedly appears to be an important negative regulator. These results may be relevant clinically for patients with SCID who have undergone hematopoietic stem cell transplantation and for patients who might be treated with a JAK3 Inhibitor.