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.

Keywords: ER stress; T cells; UPR; protein folding.

Figure 1

The role of unfolded protein response (UPR) in cell survival upon induction of ER stress. GRP78 is normally associated with PERK, IRE1, and ATF6. GRP78 disassociates from these molecules and binds to unfolded proteins as they accumulate, keeping them sequestered in the ER. Recruitment of GRP78 away from these molecules leads to their activation. PERK dimerizes and auto-phosphorylates upon removal of GRP78. It then phosphorylates eIF2α, which leads to inhibition of translation for most proteins, while UPR specific translation increases. One of those molecules upregulated is ATF4, which functions as a transcription factor and promotes the expression of proteins important in stress response. Upon release of GRP78, ATF6 travels to the Golgi where it is cleaved by S1P and S2P, resulting in a fragment that is active in promoting gene transcription. IRE1 dimerizes and auto phosphorylates as well upon removal of GRP78. It then can splice Xbp-1 mRNA, allowing for the production of a transcription factor that works in tandem with ATF6 to promote genes involved in protein folding and degradation. IRE1 activates the regulated IRE1-dependent decay (RIDD) pathway which results in the degradation of mRNAs, which reduces the load in the ER. All of these pathways promote cell survival.

Figure 2

The role of UPR in cell death upon prolonged ER stress. Prolonged activation of UPR can promote apoptosis. Dimerization and phosphorylation of PERK promotes ATF4, which activates CHOP and subsequently apoptosis. ATF6 can also promote upregulation of CHOP. IRE1α can promote apoptosis via activation of JNK and via degradation of pro-survival RNAs by RIDD.

Figure 3

Roles for UPR molecules in T cells. UPR associated proteins play important roles at all stages in the life of a T cell. Proteins in black appear to play a direct role in T cells, while proteins in red promote effector functions when the T cell is placed in a less than optimal environment (i.e., reduced glucose metabolism, amino acid deprivation, oxidizing environment, etc.). Proteins with a question mark may play a role, but further studies need to be embarked upon.