Signaling of c-kit in dendritic cells influences adaptive immunity.
The 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 granulocytes, mast cells, and of eosinophils in particular, by c-kit ligation has long been known to result in degranulation with concomitant release of pro-inflammatory mediators, including cytokines. However, recent work from a number of laboratories, including our own, highlights previously unappreciated functions for c-kit in immunologic processes. These novel findings strongly suggest that signaling through the c-kit-SCF axis could have a significant impact on the pathogenesis of diseases associated with an immunologic component. In our own studies, c-kit upregulation on dendritic cells via T helper (Th)2- and Th17-inducing stimuli led to c-kit activation and immune skewing toward these T helper subsets and away from Th1 responses. Others have shown that dendritic cell treatment with inhibitors of c-kit activation, such as imatinib mesylate (Gleevec), favored breaking of T-cell tolerance, skewing of responses toward production of Th1 cytokines, and activation of natural killer cells. These data all indicate that deeper understanding of, and ability to control, the c-kit-SCF axis could lead to improved treatment modalities aimed at redirecting unwanted and/or deleterious immune responses in a wide variety of conditions.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. rayp@pitt.edu
Prabir
P
Ray
Nandini
N
Krishnamoorthy
Timothy B
TB
Oriss
Anuradha
A
Ray
D056704:Adaptive Immunity / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D020033:Protein Isoforms; D051880:Receptors, Notch; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit