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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3227-3233.
Prepublished online as a Blood First Edition Paper on July 14, 2005; DOI 10.1182/blood-2005-02-0769.
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Submitted February 24, 2005
Accepted June 16, 2005
Jak3 negatively regulates dendritic cell cytokine production and survival
Kunihiro Yamaoka*, Booki Min, Yong-Jie Zhou, William E Paul, and John J O'Shea
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institute of Health, Bethesda, MD, USA
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA
* Corresponding author; email: yamaokak{at}mail.nih.gov.
Cytokines are critical in regulating the development and function of diverse cells. Jak3 is a tyrosine kinase expressed in hematopoietic cells, which associates with the common gamma receptor ( c) 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 c 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 pro-apoptotic proteins. Jak3-/- DCs exhibited normal antigen uptake and up-regulation of co-stimulatory molecules. However, Jak3-/-DCs produced more IL-12 and IL-10 in response to Toll-like receptor ligands, which correlated with enhanced 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 SCID patients who have undergone hematopoietic stem cell transplantation and for patients treated with Jak3 inhibitor.
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