Cellular Stress in the Context of an Inflammatory Environment Supports TGF-β-Independent T Helper-17 Differentiation

Abstract

SummaryT helper-17 (Th17) cells are associated with inflammatory disorders and cancer. We report that environmental conditions resulting in cellular stress, such as low oxygen, glucose, and isotonic stress, particularly enhance the generation of Th17 cells. Pharmacological inhibition of cell stress reduces Th17 cell differentiation while stress inducers enhance the development of Th17 cells. The cellular stress response results in Th17 cell development via sustained cytoplasmic calcium levels and, in part, XBP1 activity. Furthermore, in an inflammatory environment, conditions resulting in cell stress can bring about de novo Th17 cell differentiation, even in the absence of transforming growth factor β (TGF-β) signaling. In vivo, cell stress inhibition enhances resistance to Th17-mediated autoimmunity while stress-exposed T cells enhance disease severity. Adverse metabolic environments during inflammation provide a link between adaptive immunity and inflammation and may represent a risk factor for the development of chronic inflammatory conditions by facilitating Th17 cell differentiation.

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…This result could be attributed to XBP-1-dependent defects in dendritic cell-derived type I IFN signaling, which regulates T-cell survival, 10,66 from chemotactic signals such as CXCL16 produced by nonhematopoietic cells, also regulated by XBP-1, 67 or from antibody-mediated cutaneous infiltration of pathogenic Th17 cells. 29,65 In spleens, frequency of total granulocytes was significantly reduced after B-I09 administration in the B10.D2 to BALB/c model (data not shown), in agreement with previous reports indicating that XBP-1 is critically involved in the differentiation and recruitment of granulocyte subsets into tissues leading to inflammatory fibrosis, 11,68,69 and that these subsets are involved in cGVHD. 70,71 Current leading therapies for cGVHD directly target B cells or T cells, 31,60 whereas the current study and previous literature suggest that inhibition of the IRE-1a/ XBP-1 pathway via B-I09 could directly impact other cell subsets involved in cGVHD development in addition to B cells and T cells, 65 such as dendritic cells, 10 granulocytes, 11 and even nonhematopoietic cells.…”

“…Supporting our findings, a recent report found experimentalautoimmune-encephalitis development was significantly delayed in mice prophylactically treated with an ER stress inhibitor (tauroursodeoxycholic acid); however, experimental autoimmune encephalitis was not ameliorated with delayed administration because of no effect on early Th17 differentiation. 65 In our study, prophylactic B-I09 reduced infiltration of donor CD4…”

“…Along these lines, prophylactically targeting the IRE-1a/XBP-1 pathway using B-I09 or using XBP-1 KO B cells as APCs in vitro did not impair the GVL effect or antitumor functions of T cells in agreement with previous reports that XBP-1 deficiency had little to no direct impact on T-cell responses against infection and did not impair proliferation, activation, or differentiation of Th1 and Th2 cells. 16,65,72,73 Furthermore, administration of B-I09 in a previous study was able to directly inhibit tumor growth of B-cell leukemia, lymphoma, and multiple myeloma. 2 Thus, inhibition of IRE-1a/XBP-1 in vivo likely does not have a direct impact on antitumor functions in T cells.…”

Insights Into the Role of Endoplasmic Reticulum Stress in Infectious Diseases

“…A recent report suggests that XBP-1 is important for the differentiation of Th17 cells (26). Interestingly, it is known that the IRE1-XBP-1 pathway is activated by acute infection and is required for T cell differentiation (27).…”

At the crossway of ER‐stress and proinflammatory responses

“…T helper‐17 (Th17) cells proliferation, which is associated with autoimmune diseases and cancer, is considerably boosted by the stress caused by hypoxia or low glucose concentration. Sustained cytoplasmic calcium levels and XBP1 activity synergize to enhance Th17 proliferation, and can even compensate for the inhibitory effect of transforming growth factor ß (TGF‐ß) on their differentiation . Dendritic cells (DCs) have also been shown to rely on UPR to maintain steady‐state homeostasis and gain their unique immunostimulatory function.…”