Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Abstract

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

“…S1), which were sorted to >98% purity. CCR6 is the receptor for the mucosal chemokine CCL20 and CCR6 has been identified on Th17 cells by several groups (5, 23). Consistently, we found that CD4+CCR6+, but not CD4+CCR6−, are IL-17A producing Th17 cells (Fig.…”

“…In contrast, reports on the glucocorticoid sensitivity of Th17 cells are conflicting. Two reports suggest that IL-17 may be increased by glucocorticoids (2, 5). However, the number of sub-epithelial IL-17A-expressing cells was reported to be decreased by glucocorticoids in the airways of a cohort of patients with moderate-severe asthma (6) while studies in two separate groups of moderate-to-severe asthmatic patients found no inhibition of IL-17A cytokine expression by glucocorticoids (7, 8).…”

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

“…17,48 Because steroid treatment is the mainstay of management for chronic GVHD, this clearly warrants further investigation in allo-SCT recipients, and serendipitously, CsA treatment has been proposed to successfully treat this steroid-resistant pathogenic Th17 subtype in autoimmunity. 17,48 In the setting of acute GVHD, a recent study found that acute GVHD breaking through immune suppression was typified by T-cell persistence, as well as pro-inflammatory and Th/Tc17 transcriptional biases. 49 Here, we describe a T-cell lineage highly concordant with these observations, sharing the hallmarks of persistence, highly proinflammatory phenotype, and the Th17 transcriptional program.…”

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

“…This is particularly relevant in the setting of a shift toward Th/Tc17 predominance, given that these cells have been shown to be more resistant to the proapoptotic effects of corticosteroid treatment. [56][57][58] In addition to delineating the unique mechanisms driving both hyperacute and breakthrough acute GVHD, the data presented here provide a novel resource that takes a significant step forward toward enabling personalized, evidence-based decisions in GVHD diagnosis and treatment. These data provide critical support for the shifting landscape of T-cell immunopathology as time progresses posttransplant, and the first clues about how individual transcriptomes could, in the future, be compared with this transcriptional resource to drive patient-specific GVHD diagnosis and treatment decisions.…”