Binding of the receptor tyrosine kinase, c-kit, to its ligand, stem cell factor (SCF), mediates numerous biological functions. Important roles for c-kit in hematopoiesis, melanogenesis, erythropoiesis, spermatogenesis, and carcinogenesis are well documented. Similarly, activation of mast cells and eosinophils by c-kit ligation has long been known to result in degranulation with concomitant release of pro-inflammatory mediators including cytokines. This review will highlight a recently discovered function of c-kit in regulating the adaptive immune responses with relevance to allergic diseases.
Recent studies in a number of laboratories including our own highlight the previously unappreciated functions for c-kit in immunological processes. Increased expression of c-kit and its ligand, SCF, on dendritic cells by Th2/Th17-inducing stimuli leads to c-kit activation and immune skewing toward these subsets and away from Th1 responses. Treatment of dendritic cells with inhibitors of c-kit activation such as imatinib mesylate (Gleevec) induces breach of T-cell tolerance, skewing of responses toward Th1, and activation of natural killer cells.
Taken together, these observations suggest that the c-kit/SCF axis may be a useful target for redirecting deleterious immune responses in various disease settings, including allergic diseases that are often associated with Th2 and Th17 responses.
aDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
bBrigham and Women's Hospital, Harvard Institute of Medicine, Boston, Massachusetts
cDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Correspondence to Anuradha Ray, PhD, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA. Tel: +1 412 802 3191; fax: +1 412 692 3219; e-mail: firstname.lastname@example.org