Abstract
Purpose: :
Pathogenic or nonpathogenic Th17 cells have been reported to develop when pre-sensitized CD4 cells were polarized by either IL-23 or IL-6/TGF-β, respectively, during activation with their target antigen (McGeachy et al, Nat. Immunol.,2007). We reported, however, that naïve CD4 cells differentiate into pathogenic Th17 when polarized with IL-6/TGF-β during activation with their antigen, without IL-23 (Shi et al. J. Immunol.2009). The present study was aimed at investigating the acquisition of pathogenicity by Th17 generated from naïve CD4 cells.
Methods: :
Naïve CD4 cells from TCR transgenic mice specific to hen egg lysozyme (HEL) were polarized with IL-6/TGF-β and, concurrently, were activated either with HEL presented by APC ("HEL/APC"), or with plate-bound anti-CD3/CD28 Abs ("PbAb"). Pathogenicity was assessed by the capacity of Th17 cells to induce inflammation in eyes of recipient mice expressing HEL in their lens.
Results: :
HEL/APC Th17, but not PbAb Th17, induced inflammation in the recipients’ eyes. Unlike with pre-sensitized Th17, soluble IL-23 does not participate in pathogenicity acquisition by naïve CD4 cells: no pathogenicity was induced by adding IL-23 to cultures generating PbAb Th17. Furthermore, Abs against IL-23 or IL-23R did not inhibit acquisition of pathogenicity in cultures generating HEL/APC Th17. PbAb Th17 acquired pathogenicity, however, when co-cultured with HEL/APC. Importantly, the naïve CD4 cells did not acquire pathogenicity when co-cultured with activated APC alone, or when separated from the HEL presenting cells by a semi-permeable membrane.
Conclusions: :
Unlike pre-sensitized CD4 cells, naïve CD4 polarized toward Th17 phenotype acquire pathogenicity only by direct interaction with APC presenting the Ag, with no apparent involvement of soluble IL-23. We suggest that the Th17 lymphocytes derived from naive CD4 cells participate in pathogenic and other immune processes, along with the IL-23 dependent Th17 cells.
Keywords: inflammation • cell-cell communication • immunomodulation/immunoregulation