Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the β2‐adrenergic receptor (ADRB2) on primary human CD8⁺ effector memory T cells. Treatment of both human and murine CD8⁺ T cells with NE decreased IFN‐γ and TNF‐α secretion and suppressed their cytolytic capacity in response to T‐cell receptor (TCR) activation. The effects of NE were specifically reversed by β2‐specific antagonists. Adrb2^−/− CD8⁺ T cells were completely resistant to the effects of NE. Further, the ADRB2‐specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8⁺ T cells. While both TCR activation and stimulation with IL‐12 + IL‐18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN‐γ secretion in response to IL‐12 + IL18. Finally, the long‐acting ADRB2‐specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8⁺ T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8⁺ T‐cell function and underscores the novel role this pathway plays in adaptive T‐cell responses to infection.

Upper respiratory viral infections are a major etiologic instigator of allergic asthma, and they drive severe exacerbations of allergic inflammation in the lower airways of asthma sufferers. Rhinovirus (RV), in particular, is the main viral instigator of these pathologies. Asthma exacerbations due to RV infections are the most frequent reasons for hospitalization and account for the majority of morbidity and mortality in asthma patients. In both critical care and disease control, long- and short-acting β2-agonists are the first line of therapeutic intervention, which are used to restore airway function by promoting smooth muscle cell relaxation in bronchioles. While prophylactic use of β2-agonists reduces the frequency and pathology of exacerbations, their role in modulating the inflammatory response is only now being appreciated. Adrenergic signaling is a component of the sympathetic nervous system, and the natural ligands, epinephrine and norepinephrine (NE), regulate a multitude of autonomic functions including regulation of both the innate and adaptive immune response. NE is the primary neurotransmitter released by post-ganglionic sympathetic neurons that innervate most all peripheral tissues including lung and secondary lymphoid organs. Thus, the adrenergic signaling pathways are in direct contact with both the central and peripheral immune compartments. We present a perspective on how the adrenergic signaling pathway controls immune function and how β2-agonists may influence inflammation in the context of virus-induced asthma exacerbations.

Background/Objectives: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways. Methods: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming. Results: All CAR T cells exhibited activation of NF-κB–centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes. Conclusions: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism.

The heterogeneity of cancer necessitates developing a multitude of targeted therapies. We propose the view that cancer drug discovery is a low rank tensor completion problem. We implement this vision by using heterogeneous public data to construct a tensor of drug-target-disease associations. We show the validity of this approach computationally by simulations, and experimentally by testing drug candidates. Specifically, we show that a novel drug candidate, SU11652, controls melanoma tumor growth, including BRAF ^WT melanoma. Independently, we show that another molecule, TC-E 5008, controls tumor proliferation on ex vivo ER+ human breast cancer. Most importantly, we identify these chemicals with only a few computationally selected experiments as opposed to brute-force screens. The efficiency of our approach enables use of ex vivo human tumor assays as a primary screening tool. We provide a web server, the Cancer Vulnerability Explorer (accessible at https://cavu.biohpc.swmed.edu ), to facilitate the use of our methodology.