Immune Regulation by Glucocorticoids Can Be Linked to Cell Type–dependent Transcriptional Responses
Franco LM, Gadkari M, Howe KN, et al. J Exp Med. 2019;216(2):384–406.
Glucocorticoids have been a mainstay for treatment of a range of inflammatory disorders for >60 years.1 While widely used, the biological basis underpinning their immunoregulatory effects is still poorly described.
In general, glucocorticoids are known to act by binding to the glucocorticoid receptor (GR) in the cytosol, causing GR dimerization and subsequent translocation to the nucleus, where the ligand-bound GR binds to glucocorticoid response elements on the DNA increasing their transcriptional activity.2 Additionally, glucocorticoids are known to interfere with the activity of other transcription factors such as NF-êB.3 The genomic location of GR binding has been shown to differ greatly among different cell types. To further investigate how glucocorticoids differentially affect different cell types, Franco et al4 interrogated the genome-wide transcriptional response to glucocorticoids in 9 distinct human cell types in vitro and used this data to create a pathway-level map of the effects of glucocorticoids across these cell types. They found that the transcriptional response of different cell types to glucocorticoids is highly varied. The number of genes that responded to glucocorticoid treatment was greater in hematopoietic cells than in nonhematopoietic cells, with neutrophils having the greatest number of responsive genes. The specific glucocorticoid-responsive genes identified were also highly variable in each cell type, even when comparing cells of similar origin. Additionally, they found no correlation between the baseline expression of a gene and the average response of that gene to glucocorticoid treatment—many genes that were expressed at comparable baseline levels in hematopoietic and nonhematopoietic cells only responded to glucocorticoid treatment in one of these 2 groups. The authors also identified specific pathways affected by glucocorticoid stimuli. With a a specific focus on B cells, Franco et al found significant upregulation of IL-10, along with significant downregulation of essential B cell receptor signaling proteins, and a decrease in toll-like receptor expression. Functional studies confirmed that glucocorticoids diminished B cell receptor and toll-like receptor signaling. Glucocorticoids also increased expression of the gene encoding BLIMP-1, which is a central part of terminal differentiation in B cells. This could be a mechanism behind the reduced B cell proliferation seen following glucocorticoid administration.
With detrimental effects of long-term glucocorticoid use well described, understanding the mechanistic pathways that underpin the immunoregulatory impact of these drugs may prove critical in finding novel agents that exert a similar response without adverse off-target effects.
Mitochondrial Complex III Is Essential for Suppressive Function of Regulatory T Cells
Weinberg SE, Singer BD, Steinert EM, et al. Nature. 2019;565(7740):495–499.
In recent years, there has been a great interest in the potential of regulatory T cell (Treg) therapy for inducing tolerance after solid organ transplantation and for the treatment of graft-versus-host disease. With many promising trials,1 questions surrounding the perpetuation of the suppressive function of Tregs postinfusion remain.
It has been shown that there are defined metabolic profiles associated with Treg differentiation and phenotype. Treg cells are largely dependent on mitochondrial metabolism and have been shown to oxidize pyruvate and lipids preferentially when compared with conventional T cells. This unique metabolic profile has been functionally linked to the suppressive phenotype of Treg cells; indeed, the plasticity of Treg suppressive function may well be linked to their metabolic plasticity.
To investigate whether Treg suppression is reliant on the mitochondrial respiratory chain, Weinberg et al2 generated mice with a Treg-specific Rieske iron-sulfur protein (RISP) knockout. RISP is an essential part of the mitochondrial respiratory chain complex III, thus ablating mitochondrial complex III function. These mice displayed substantial inflammation by the age of 3 weeks, with enlarged lymph nodes and spleens, thymic atrophy, and increased CD4+ and CD8+ T cell activation and proliferation in the spleen and lymph nodes. This phenotype is highly reminiscent of the Treg deficient Scurfy mice3; however, the number of Tregs in RISP knockout mice remained unchanged. RISP knockout Tregs demonstrated significantly reduced suppressive capacity both in vitro and in vivo. Interestingly, Foxp3 expression levels did not change, demonstrating that Treg suppressive function is reliant on mitochondrial complex III.
To further verify that this phenotype was due to a lack in mitochondrial complex III function, the authors also generated mice with a Treg-specific knockout of QPC, another essential subunit of mitochondrial complex III. A similar pattern of systemic inflammation and overt overproliferation of CD4+ and CD8+ T cells was observed, resulting in death of the mice by 3 weeks.
These data show that mitochondrial complex III function is necessary for Treg suppressive function and global immune regulation. Understanding how mitochondrial function can affect Treg suppressive potency may prove important for their use as a cellular therapy posttransplantation, given that such therapies may be rendered nonfunctional in an ischemic microenvironment.