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Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905
Costimulation by the chemokine, stromal cell-derived factor-1 (SDF-1)/CXCL12, has been shown to increase the amount of IL-10 secreted by TCR-stimulated human T cells; however, the molecular mechanisms of this response are unknown. Knowledge of this signaling pathway may be useful because extensive evidence indicates that deficient IL-10 secretion promotes autoimmunity. The human IL-10 locus is highly polymorphic. We report in this study that SDF-1 costimulates IL-10 secretion from T cells containing all three of the most common human IL-10 promoter haplotypes that are identified by single-nucleotide polymorphisms at –1082, –819, and –592 bp (numbering is relative to the transcription start site). We further show that SDF-1 primarily costimulates IL-10 secretion by a diverse population of CD45RA– ("memory") phenotype T cells that includes cells expressing the presumed regulatory T cell marker, Foxp3. To address the molecular mechanisms of this response, we showed that SDF-1 costimulates the transcriptional activities in normal human T cells of reporter plasmids containing 1.1 kb of all three of the common IL-10 promoter haplotypes. IL-10 promoter activity was ablated by mutating two nonpolymorphic binding sites for the AP-1 transcription factor, and chromatin immunoprecipitation assays of primary human T cells revealed that SDF-1 costimulation enhances AP-1 binding to both of these sites. Together, these results delineate the molecular mechanisms responsible for SDF-1 costimulation of T cell IL-10 secretion. Because it is preserved among several human haplotypes and in diverse T cell populations including Foxp3+ T cells, this pathway of IL-10 regulation may represent a key mechanism for modulating expression of this important immunoregulatory cytokine.
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1 This work was supported in part by the philanthropy of Barbara Lipps to the Mayo Clinic and by National Institutes of Health RO1 Grant GM59763 (to K.E.H.).
2 Address correspondence and reprint requests to Dr. Karen E. Hedin, Mayo Clinic, Department of Immunology, Guggenheim Building, 3rd Floor, 200 First Street Southwest, Rochester, MN 55905. E-mail address: hedin.karen{at}mayo.edu
3 Abbreviations used in this paper: SDF-1, stromal cell-derived factor-1; HIV-1, HIV type-1; SNP, single-nucleotide polymorphism; ChIP, chromatin immunoprecipitation.
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  D. D. Sloan and K. R. Jerome Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10 J. Virol., November 15, 2007; 81(22): 12504 - 12514. [Abstract] [Full Text] [PDF]
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