The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

BackgroundT cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in activated CD4+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4μ8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4μ8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma.ResultsTreatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4μ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot.ConclusionThese data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4μ8c blocks its expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.Electronic supplementary materialThe online version of this article (10.1186/s12865-018-0283-7) contains supplementary material, which is available to authorized users.

TH2 cells are crucial in immune responses against extracellular pathogens; however, they can play a predominant role in a number of diseases due to inappropriate IL-4, IL-5, and IL-13 cytokine expression. Therefore, understanding how these cells develop and regulate their effector functions is of great importance. In response to an excess of unfolded proteins, serine-threonine kinase Inositol-Requiring Enzyme 1 α or IRE1α activates the unfolded protein response, UPR, which promotes increased protein folding capacity. T cell activation induces ER stress, and inhibition of IRE1α RNase activity in activated primary cells, via treatment of the cells with the commercially available drug 4μ8c, results in the reduction of IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4μ8c could inhibit TH2 cytokines in established TH2 cells. Treatment of a mouse TH2 cell line and differentiated human TH2 cells with 4μ8c results in inhibition of IL-5 and IL-13, but not IL-4 as measured by ELISA. The reduced cytokine expression is not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells appear to produce cytokines IL-5 and IL-13 as measured by flow cytometry. This suggests that the inhibition of these cytokines is due to post-translational processes. IL-5 and IL-13 produced by TH2 cells are critical for promoting chronic, inflammatory asthma, and 4μ8c blocks their expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of these cytokines in a disease model. This work is supported by the NSU Faculty Research Council grant and OK-INBRE NIH P20GM103447.