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Guangpu Shi, Jenna D. Lovaas, Cuiyan Tan, Barbara P. Vistica, Eric F. Wawrousek, Mehak K. Aziz, Rachael C. Rigden, Rachel R. Caspi, Igal Gery; Cell-cell Interaction with APC, not IL-23, is Required for Naive CD4 Cells to Acquire Pathogenicity During Th17 Lineage Commitment. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5487.
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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.
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.
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.
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.
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