CD4 T-cell-intrinsic IL6, but not T-cell-intrinsic IL1β, is required for Th17 differentiation and acquisition of effector resistance to immune suppression

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B604
Abstract ID: 4657

Presenting Author:
Chakrapani Vemulawada , Postdoc at Univ. of Iowa

Abstract:

CD4 T-helper 17 (Th17) cells play important roles in infection, cancer and autoimmunity.  Different combinations of IL6, IL1β, IL21, IL23, and TGFβ can aid in the differentiation of naïve CD4 T cells into Th17s.  We have shown that CD4 T cells differentiated to Th17 develop resistance to suppression by CD8 T cells and this can be reversed with anti-IL6 and anti-IL1β. We have detected IL6 and IL1b transcripts in purified T cells, leading us to hypothesize that T-cell-intrinsic IL6 and IL1β play a role in Th17 differentiation and development of resistance. Using CRISPR/Cas9-mediated knockdown of IL6, we observed that the absence of IL6 in naïve CD4 T cells inhibited their ability to differentiate into Th17 cells, even when IL6, IL1β, and TGFβ were provided externally. These IL6-KO cells also remained susceptible to CD8-mediated suppression. Antibody blockade of IL6 or IL6R replicated findings similar to IL6-KO cells. In contrast, anti-IL1β or anti-IL1R blockade did not mimic IL6, in that T-cell-intrinsic IL1β was not essential in their ability to differentiate into Th17 or attain resistance. Interestingly, the provision of TGFβ+IL21 circumvented the need for T-cell-intrinsic IL6, suggesting that IL21 may follow an alternative pathway to induce resistant Th17 cells.  These studies provide novel insights into the biology of T-cell-intrinsic IL6, IL1β and suggest that IL6 pathways within T cells may be attractive targets for immunotherapeutic intervention.