Buchele, Vera and Abendroth, Benjamin and Buettner-Herold, Maike and Vogler, Tina and Rothamer, Johanna and Ghimire, Sakhila and Ullrich, Evelyn and Holler, Ernst and Neurath, Markus F. and Hildner, Kai (2018) Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis. FRONTIERS IN IMMUNOLOGY, 9: 1138. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF+) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF+ T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (ROR gamma t) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells' ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, ROR gamma t-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/ROR gamma t double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by ROR gamma t-deficient donor T cells. Finally, in analogy to our murine studies, colonic RORC expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling-and ROR gamma t-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | VERSUS-HOST-DISEASE; CHRONIC INTESTINAL INFLAMMATION; CYTOKINE GM-CSF; INNATE LYMPHOID-CELLS; DENDRITIC CELLS; CROHNS-DISEASE; TH17 CELLS; AUTOIMMUNE NEUROINFLAMMATION; BOWEL-DISEASE; T(H)17 CELLS; retinoic acid-related orphan receptor gamma t; interleukin-23 receptor; T helper 17 cells; granulocyte-macrophage colony-stimulating factor; basic leucine zipper transcription factor ATF-like; intestinal graft-versus-host disease; colitis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2020 12:16 |
| Last Modified: | 09 Mar 2020 12:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14557 |
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