![]() The lack of palmitoylation was suggested as the cause of this human disease. A non-palmitoylable C564R Zap70 mutant, which has been reported in a patient suffering from immunodeficiency, is incapable of propagating TCR signaling and activating T cells. Recently, it has been proposed that C564, located in the kinase domain of Zap70, is palmitoylated. These events are crucial to drive T-cell development and T-cell activation. Zap70 propagates the TCR signal by phosphorylating two important adaptor molecules, LAT and SLP76, which orchestrate the assembly of the signaling complex, leading to the activation of PLCγ1 and further downstream pathways. Therefore, in this review, we summarize the latest research on CD8 ⁺ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8 ⁺ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8 ⁺ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy.Īlterations in both the expression and function of the non-receptor tyrosine kinase Zap70 are associated with numerous human diseases including immunodeficiency, autoimmunity, and leukemia. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8 ⁺ TILs in the case of targeting T cell’s metabolism to synergize cancer immunotherapy. The origin of dysfunctional CD8 ⁺ TILs shares important features with memory T cell’s precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8 ⁺ TILs remains elusive. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8 ⁺ TILs dysfunction. It is reported that tumor-infiltrating CD8 ⁺ T lymphocytes (CD8 ⁺ TILs) burn fats to restore their impaired effector function due to the lack of glucose. Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3ζ transmembrane helix, thereby activating the TCR-CD3 complex in human cells. The structures reveal that cholesterol molecules act like a latch to lock CD3ζ into an inactive conformation in the membrane. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. ![]() The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. ![]()
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