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B. P. Vistica, G. Shi, J. Lovaas, C. Tan, M. Aziz, I. Gery; A Comparison of the Biological Activities of the Pathogenic and Non-Pathogenic Subsets of the Th17 Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):822.
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© ARVO (1962-2015); The Authors (2016-present)
Th17 cells play a major role in immunopathogenic processes, including inflammatory eye conditions in humans and experimental animals. McGeachy et al, (Nat. Immunol., 2007) showed that the population of Th17 in experimental autoimmune encephalomyelitis is heterogenic, with one subset being non-immunopathogenic. We reported at ARVO 2009 that these two subsets are also present in our experimental system of ocular inflammation. Here, we further characterize features that distinguish each of these two sub-populations of Th17.
Naive CD4+ cells were isolated from hen egg lysozyme (HEL) -specific TCR transgenic mice and cultured with cytokines and antibodies used to polarize cells toward Th17. Pathogenic "HA" Th17 were generated by activation with HEL and APC whereas non-pathogenic "PbAb" Th17 were generated by activating the cells with plate-bound anti-CD3/CD28 antibodies. Cytokine levels of the cultured cells were determined by ELISA and intracellular staining. Immunopathogenicity of the Th17 cells was determined by their capacity to induce ocular inflammation in recipient mice expressing HEL in their lens. Development of ocular inflammation was determined by routine histology.
(i) McGeachy et al reported that immunopathogenic Th17 generated by antigen activation did not produce IL-10. In our system, however, HA Th17 produced IL-10 with levels similar to those made by the nonpathogenic PbAb Th17. Further, intracellular staining showed co-production of IL-10 and IL-17 by the HA cells; (ii) when injected into naïve recipients, HA Th17 resembled Th1 cells by homing to the recipient spleen where they underwent vigorous proliferation. In contrast, PbAb cells failed to demonstrate a similar proliferative response in the recipient spleen; (iii) PbAb cells exhibited immunoregulatory activity by their capacity to inhibit the severity of ocular inflammation when co-injected along with disease-inducing HA Th17 cells; (iv) IL-23R is essential for the development and maintenance of Th17 pathogenicity and surprisingly, the pathogenic HA Th17 expressed lower levels of IL-23R than did the non-pathogenic PbAb cells following 2 or 3 days of activation.
Our system made it possible to further dissect the unusual phenomenon of pathogenic and non-pathogenic subsets of T-helper cells selectively producing IL-17.
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