Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function.

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.

Treatment of established TH2 cells with 4µ8c, an inhibitor of IRE1α, blocks IL-5 but not IL-4 secretion.

BACKGROUND: T 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. RESULTS: Treatment 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. CONCLUSION: These 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.