Metabolic waypoints during T cell differentiation.

This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor-major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process. Firstly, metabolites act as signal propagators that aid in the transmission of core activation signals, such as specific lipid species that are crucial at the immune synapse. Secondly, metabolites also function as unique signals that influence immune differentiation pathways, such as amino acid-induced mTORC1 signaling. Metabolites also play a substantial role in epigenetic remodeling, by directly modifying histones, altering gene expression and influencing T cell behavior. This Review discusses how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites. We underscore the integration of immunological and metabolic inputs in T cell function and suggest that metabolite availability is a fundamental determinant of adaptive immune responses.

An oncolytic virus-delivered TGFß inhibitor overcomes the immunosuppressive tumor microenvironment.

While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFNγ, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFß, which blunted IFNγ signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFßRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFß inhibition had no toxicities associated with systemic TGFß/TGFßR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer.

Histone deacetylase 3 represses cholesterol efflux during CD4+ T-cell activation.

After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.