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CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. [ABSTRACT FROM AUTHOR]

Tregs can facilitate transplant tolerance and attenuate autoimmune and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg expansion and function in vivo and to create therapeutic Treg products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naive, thymus-derived Tregs (tTregs) from human blood that promotes their differentiation into nonlymphoid tissue-resident (NLT-resident) effector Tregs, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue-resident (LT-resident) Treg phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTregs and conventional T cells (Tconvs), followed by bioinformatic comparison with published transcriptomic Treg signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promoted tTreg capacity for survival, migration, immunosuppression, and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTregs. Flow cytometry validated the presence of the TNFR2-driven tTreg signature in effector/memory Tregs from the human placenta, as opposed to blood. Thus, TNFR2 can be exploited as a driver of NLT-resident tTreg differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.

Resident memory T cells (T RM ) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103 + T RM are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intratumoral CD103 + CD8 + tumor infiltrating lymphocytes (TILs), with T RM properties, are a positive prognostic marker. To better understand the role of T RM in tumors, we performed a detailed characterization of CD8 + and CD4 + TIL phenotype and functional properties in non-small cell lung cancer (NSCLC). Frequencies of CD8 + and CD4 + T cell infiltrates in tumors were comparable, but we observed a sharp contrast in T RM ratios compared to surrounding lung tissue. The majority of both CD4 + and CD8 + TILs expressed CD69 and a subset also expressed CD103, both hallmarks of T RM . While CD103 + CD8 + T cells were enriched in tumors, CD103 + CD4 + T cell frequencies were decreased compared to surrounding lung tissue. Furthermore, CD103 + CD4 + and CD103 + CD8 + TILs showed multiple characteristics of T RM , such as elevated expression of CXCR6 and CD49a, and decreased expression of T-bet and Eomes. In line with the immunomodulatory role of the tumor microenvironment, CD8 + and CD4 + TILs expressed high levels of inhibitory receptors 2B4, CTLA-4, and PD-1, with the highest levels found on CD103 + TILs. Strikingly, CD103 + CD4 + TILs were the most potent producers of TNF-α and IFN-γ, while other TIL subsets lacked such cytokine production. Whereas, CD103 + CD4 + PD-1 low TILs produced the most effector cytokines, CD103 + CD4 + PD-1 ++ and CD69 + CD4 + PD-1 ++ TILs produced CXCL13. Furthermore, a large proportion of TILs expressed co-stimulatory receptors CD27 and CD28, unlike lung T RM , suggesting a less differentiated phenotype. Agonistic triggering of these receptors improved cytokine production of CD103 + CD4 + and CD69 + CD8 + TILs. Our findings thus provide a rationale to target CD103 + CD4 + TILs and add co-stimulation to current therapies to improve the efficacy of immunotherapies and cancer vaccines.