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

Abstract

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.

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

“…The accumulation of unfolded protein in the endoplasmic reticulum (ER) leads to cellular stress and, where unresolved, a loss of regular cell functions prompting apoptosis. Eukaryotic cells have developed an evolutionary well-conserved mechanism to clear unfolded proteins and to restore ER homeostasis, known as the unfolded protein response (UPR) 32 . The UPR comprises a tightly orchestrated collection of signalling events that are controlled by protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring protein-1α (IRE-1α), which collectively sense ER stress and alleviate the accumulation of misfolded proteins, for example, via increasing the expression of ER chaperones 33 (Supplementary Fig.…”

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

“…These findings align well with studies that have identified a role for UPR in thymocyte maturation and selection (reviewed in ref. (Kemp & Poe, 2019)). Interestingly, the observed partial block in thymocyte maturation was relatively mild despite a complete absence of CCT8 at the DP and later stages of thymocyte maturation.…”

“…The accumulation of unfolded protein in the endoplasmatic reticulum (ER) leads to cellular stress and, where unresolved, a loss of regular cell functions prompting apoptosis. Eukaryotic cells have developed an evolutionary well conserved mechanism to clear unfolded proteins and to restore ER homeostasis, known as the unfolded protein response (UPR) (Kemp & Poe, 2019). The UPR comprises a tightly orchestrated collection of signaling events that are controlled by protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring protein-1(IRE-1), which collectively sense ER stress and alleviate the accumulation of misfolded proteins, for example via increasing the expression of ER chaperones (Sano & Reed, 2013) (Figure EV 3a).…”

The Role of TRAIL/DRs in the Modulation of Immune Cells and Responses

“…Other immune effector cells known to be sensitive towards TRAIL-induced apoptosis are sub-optimal activated, ‘helpless’ CD8 + T cells upon secondary stimulation [198,204,207]; terminally differentiated cells, like T cell blasts [210,266]; plasma cells [243]; MDSCs [30,62,127]; and hematopoietic cancers (e.g., [100,188,238]). Activated immune cells greatly increase the synthesis of proteins, which can stress the endoplasmic reticulum (ER), leading to an ‘unfolded protein response’ (UPR) [267,268,269]. Similar, pathogens and chronic cell activation can cause ER stress [267,269,270].…”