Human Th17 Cells of Different Strokes: Effector Resistance to Suppression Determined by a TGFβ1-containing Differentiation Milieu and Resultant IFNγ Downregulation. 

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B606
Abstract ID: 4974

Presenting Author:
Michael P Crawford , Research Assistant at Univ. of Iowa

Abstract:

^{CD4 T-helper 17 (Th17) cells play vital roles in infection, cancer and autoimmunity.  We have shown that Th17s differentiated under the influence of IL1β, IL6 and TGFβ1 acquire resistance to suppression by CD8 T cells, partly mediated through action of IL17. In this study, we differentiated ex vivo naïve CD4 T cells into IL17-producing “Th17 cells” under the influence of 9 different cytokine combinations. We observed that conditions which included TGFβ1 in combination with other cytokines resulted in Th17s with intrinsic resistance to CD8 T cell-mediated suppression, as opposed to Th17 cells differentiated without TGFβ1. Unsupervised analysis using bulk RNA-sequencing also results in two clusters, where the 4 TGFβ1-containing conditions were genetically indistinct from each other. To further isolate genes relevant to effector resistance, we compared various types of resistant CD4 T cells from different studies to non-resistant CD4 T cells.  RNA-Seq analysis showed 12 upregulated genes and 11 downregulated genes.  Interestingly, IFNγ was significantly downregulated in the resistant CD4 phenotype.  Using Bioplex protein measurements as well as QPCR, we confirmed that IFNγ protein and message were downregulated in resistant cells.  These studies reveal a novel interplay between TGFβ1, IL17 and IFNγ-dependent pathways that may underlie immune resistance and serve as an attractive target for immunotherapeutic strategies in the future.}