DUBs may regulate CD4+ T cell differentiation through controlling cytokine production during the early phase of T cell activation or regulating the lineage transcription factors during the subsequent phase of differentiation
January 27, 2022
DUBs may regulate CD4+ T cell differentiation through controlling cytokine production during the early phase of T cell activation or regulating the lineage transcription factors during the subsequent phase of differentiation. proliferation and cytokine projection. Thus, CYLD is usually a crucial unfavorable regulator of TCR activation and homeostasis. In line with these findings, a recent study demonstrates that this CYLD deficiency promotes CD8+ T cell responses and renders mice more resistant to experimental cerebral malaria (ECM) induction in a murine model . Like CYLD, USP18 targets the ubiquitin-dependent kinase TAK1. It appears that CYLD is usually more important for controlling the ubiquitination and signaling function of TAK1 under homeostatic conditions , whereas USP18 inhibits TCR-stimulated TAK1 ubiquitination and signaling . The USP18 deficiency promotes TCR/CD28-stimulated activation of the TAK1 downstream kinases IKK and JNK as well as the transcription factors NF-B and NFAT, resulting in hyper induction of genes encoding IL-2 and IFN. As will be discussed in the following section, USP18 also plays an important role in regulating CD4+ T cell differentiation. A20 is usually another DUB that negatively regulates the NF-B signaling pathway as well as other inflammatory pathways  (Fig. 2). Although A20 has been most extensively studied in innate immune cells, emerging evidence suggests that this DUB also plays an important role in the regulation of T cell activation and survival. A20 has an important role in regulating CD8 T cell responses . This function of A20 involves inhibition of NF-B signaling, and A20 deletion in mature T cells causes hyper production of IL-2 (Z)-2-decenoic acid and IFN in CD8+ T cells through increased NF-B activation. High levels of A20 expression in tumor-infiltrating CD8+ T cells are associated with poor anti-tumor immunity, and deletion of A20 increases the capability of CD8 T cells to reject tumors . Another study suggests that A20 has opposing roles in the regulation of primary and memory responses of CD8+ T cells . Mice with T cell-specific A20 deletion mount stronger immune responses during primary contamination with reinfection due to profound loss of pathogen-specific effector and memory CD8+ T cells . A20 appears to inhibit the expression of the death receptor Fas (also called CD95) and prevent Fas-induced CD8+ T cell apoptosis . A20 also plays a crucial role in regulating the survival of activated CD4+ T cells, which involves deconjugation of ubiquitin chains from K5 of RIPK3 . The K5 ubiquitination of RIPK3 serves as a trigger for formation of RIPK1-RIPK3 complexes that are required for the induction of necroptotic cell death . Thus, A20 deficiency promotes RIPK3 ubiquitination and formation of the RIPK1-RIPK3 complexes, causing exacerbated CD4+ T cell death . Consistently, RIPK3 deficiency restores the survival of A20-deficient T cells and partially rescues the perinatal death of A20-KO mice . Another mechanism of A20-mediated T cell survival is usually through regulation of autophagy . A20 promotes autophagy in CD4+ T cells by inhibiting the activation of mTOR complex 1 (mTORC1), a kinase that serves as a major inhibitor of autophagy . Consistent with an earlier study that TRAF6-mediated K63 ubiquitination of mTOR triggers its activation , A20 inhibits mTOR through deconjugating its polyubiquitin chains . While several DUBs negatively regulate TCR-stimulated NF-B signaling, the DUB USP9X serves as a positive regulator of this pathway . USP9X physically interacts with Bcl10 in the CBM complex and inhibits TCR-stimulated Bcl10 ubiquitination. USP9X appears to remove K48-linked ubiquitin chains from Bcl10. Interestingly, however, USP9X knockdown does not promote Bcl10 degradation despite its increased K48 ubiquitination. The ubiquitination of Bcl10 seems to interfere with its association with CARMA1 and MALT1 . The NFAT (Z)-2-decenoic acid signaling pathway is also subject to (Z)-2-decenoic acid ubiquitin-dependent regulation. Recent studies demonstrate that this activated form of NFATc2 is usually conjugated with K48 ubiquitin chains by the E3 ubiquitin ligase MDM2 and targeted for proteasomal degradation  (Fig. 2). Pharmacological inhibition or genetic deletion of MDM2 enhances nuclear NFATc2 along with T cell activation, which is usually associated with (Z)-2-decenoic acid hyper induction of cytokines, including IL-2 and IFN. Interestingly, this unfavorable mechanism of NFAT regulation also requires a DUB, USP15, which functions by stabilizing MDM2. Along with TCR/CD28 stimulation, MDM2 is usually transiently downregulated due to ubiquitin-dependent degradation, and the MDM2 degradation is usually greatly accelerated in USP15-deficient T cells. USP15 physically interacts with MDM2 and inhibits the ubiquitination and degradation of MDM2. Thus, USP15 can be considered a partner of MDM2 in MAP3K10 the regulation of NFAT ubiquitination and T cell activation (Fig. 2). Since USP15 also stabilizes MDM2 in cancer cells, in which MDM2 serves as a major survival factor, ablation of USP15 appears to inhibit tumor growth by both promoting anti-tumor T cell responses.