Immunology of the eye

Oral

il-17a Dampens Autoimmune Disease by Inhibiting the Expression of il-17 Lineage Cytokines Through a Negative Feedback Loop Involving il-24

Friday, June 16
6:15 PM - 7:30 PM

The Th17 response has been associated with autoimmune diseases in patients and in animal models, including autoimmune uveitis and its experimental counterpart, EAU. Paradoxically, however, IL-17A treatment given to EAU-challenged mice was reported to ameliorate the disease (PMID: 19234216) and clinical trials targeting IL-17A in uveitis have been largely disappointing (PMID: 25648267). Here, we investigated susceptibility to uveitis of spontaneously uveitic R161H mice (IRBP T cell receptor transgenic, PMID: 23810578) crossed onto the IL-17A-/- background. Surprisingly, IL-17A-/- R161H mice developed essentially undiminished uveitis. Moreover, IL-17A-/- R161H T cells, polarized to Th17 and infused into wild type recipients, induced similar disease to IL-17A-sufficient R161H T cells. These Th17-polarized IL-17A-/- R161H T cells produced elevated amounts of other Th17 lineage cytokines, namely, IL-17F, GM-CSF and IL-22, and this was reversed by supplementing the cultures with recombinant IL-17A. RNAseq analysis revealed that the IL-17A-/- T cells expressed lower levels of IL-24 compared to their IL-17A sufficient counterparts. Mechanistic studies in vitro indicated a negative feedback loop where IL-17A induces Th17 cells to produce IL-24, which subsequently suppresses production of Th17 lineage cytokines. Studies in vivo showed that injection of recombinant IL-24 ameliorated adoptive Th17-induced EAU, and conversely, silencing IL-24 expression in the adoptively transferred Th17 cells increased their pathogenicity and enhanced disease severity. Our data suggest that IL-17A exerts a negative feedback on Th17 cells by inducing IL-24, which limits the expression of Th17-related cytokines and dampens Th17 effector pathogenicity.

Wai Po Chong

NIE/NIH, Bethesda, MD, USA and ZOC, Guangzhou, China

Presentation(s):

    Send Email for Wai Po Chong

    Kumarkrishna Raychoudhuri

    NEI/NIH , Bethesda, MD, USA

    Presentation(s):

      Send Email for Kumarkrishna Raychoudhuri

      Reiko Horai

      NIE/NIH, Bethesda, MD, USA

      Presentation(s):

        Send Email for Reiko Horai

        Phyllis B. Silver

        NIE/NIH, Bethesda, MD, USA

        Presentation(s):

          Send Email for Phyllis Silver

          Yingyos Jittayasothorn

          NIE/NIH, Bethesda, MD, USA

          Presentation(s):

            Send Email for Yingyos Jittayasothorn

            Chi Chao Chan

            NIE/NIH, Bethesda, MD, USA

            Presentation(s):

              Send Email for Chi Chao Chan

              Jun Chen

              NIE/NIH, Bethesda, MD, USA and ZOC, Guangzhou, China

              Presentation(s):

                Send Email for Jun Chen

                Rachel R. Caspi

                NIE/NIH, Bethesda, MD, USA

                Presentation(s):

                  Send Email for Rachel Caspi


                  Assets

                  il-17a Dampens Autoimmune Disease by Inhibiting the Expression of il-17 Lineage Cytokines Through a Negative Feedback Loop Involving il-24



                  Attendees who have favorited this

                  Send Email for il-17a Dampens Autoimmune Disease by Inhibiting the Expression of il-17 Lineage Cytokines Through a Negative Feedback Loop Involving il-24