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 (RORγt) 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, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/RORγt 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 RORγt-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 RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
Highlights
Despite exerting crucial barrier-protective functions under homeostatic conditions, interleukin-17a (IL-17a) producing T helper (Th17) cells are the most-abundant subpopulation within intestinal inflammatory lesions found in patients with inflammatory bowel diseases (IBDs) and acute manifestation of gastrointestinal graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation [1, 2]
We reported that acute inflammatory tissue manifestation of GvHD in the lower gastrointestinal tract depends on the ability to express basic leucine zipper transcription factor ATF-like (BATF) within donor T cells [17]
We assessed the functional contribution of these T cells and found that combined blockade of interleukin-7 receptor (IL-7R)/IL-7 interaction and granulocyte-macrophage colony-stimulating factor (GM-CSF) proved to be very effective in harnessing GvHD driven colonic inflammation
Summary
Despite exerting crucial barrier-protective functions under homeostatic conditions, interleukin-17a (IL-17a) producing T helper (Th17) cells are the most-abundant subpopulation within intestinal inflammatory lesions found in patients with inflammatory bowel diseases (IBDs) and acute manifestation of gastrointestinal graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1, 2]. We and others have previously demonstrated that T cells with a genetic inactivation of Th17 cell regulating transcription factors retinoic acid-related orphan receptor gamma t (RORγt), interferon regulatory factor-4, signal transducer and activator of transcription 3 (STAT3), or basic leucine zipper transcription factor ATF-like (BATF) uniformly failed to induce colitis in a series of syngeneic murine IBD models supporting the concept that harnessing unleashed intestinal inflammation can be achieved by targeting Th17 cell biology [7,8,9,10,11] In line within this assumption, genetic inactivation or blockage of interleukin-23 (IL-23) knowingly absolutely required for the occurrence of Th17 cells in vivo were shown to mitigate colitis in preclinical model systems and be effective in treating IBD [5, 12, 13]. In the light of the notion provided by recent studies showing in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, that GM-CSF-expressing T cells are driven by IL-23, express the master regulator of Th17 development RORγt and putatively represent a Th17 cell subset [22, 23], our current study was intended to characterize [1] the developmental relationship between Th17 and GM-CSF+ T cells based on the dependency on upstream and transcriptional signals and [2] the subset-specific, functional contribution to the manifestation of acute GvHD-associated colitis in vivo
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