Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β₂-adrenergic receptor (β₂AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β₂AR stimulation in DC induces protein kinase A–dependent cAMP-responsive element–binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A–independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β₂AR stimulation, LPS-stimulated DC promoted the generation of CD4⁺ T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β₂AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.

γδ T cells have many known functions, including the regulation of antibody responses. However, how γδ T cells control humoral immunity remains elusive. Here we show that complete Freund’s adjuvant (CFA), but not alum, immunization induces a subpopulation of CXCR5-expressing γδ T cells in the draining lymph nodes. TCRγδ⁺CXCR5⁺ cells present antigens to, and induce CXCR5 on, CD4 T cells by releasing Wnt ligands to initiate the T follicular helper (Tfh) cell program. Accordingly, TCRδ^−/− mice have impaired germinal center formation, inefficient Tfh cell differentiation, and reduced serum levels of chicken ovalbumin (OVA)-specific antibodies after CFA/OVA immunization. In a mouse model of lupus, TCRδ^−/− mice develop milder glomerulonephritis, consistent with decreased serum levels of lupus-related autoantibodies, when compared with wild type mice. Thus, modulation of the γδ T cell-dependent humoral immune response may provide a novel therapy approach for the treatment of antibody-mediated autoimmunity.

Regulatory T cells (T_regs) promote cancer by suppressing antitumor immune responses. We found that anti-LAP antibody, which targets the latency-associated peptide (LAP)/transforming growth factor–β (TGF-β) complex on T_regs and other cells, enhances antitumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma, and glioblastoma. Anti-LAP decreases LAP⁺ T_regs, tolerogenic dendritic cells, and TGF-β secretion and is associated with CD8⁺ T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8⁺ T cells and reduces CD103⁺ CD8 T cells in draining lymph nodes and the spleen. We identified a role for CD103⁺ CD8 T cells in cancer. Tumor-associated CD103⁺ CD8 T cells have a tolerogenic phenotype with increased expression of CTLA-4 and interleukin-10 and decreased expression of interferon-γ, tumor necrosis factor–α, and granzymes. Adoptive transfer of CD103⁺ CD8 T cells promotes tumor growth, whereas CD103 blockade limits tumorigenesis. Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy.

Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (T_reg cells) that migrated to the brain and closely contacted microglia. T_reg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing T_reg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury.

Major Depressive Disorder (MDD) is increasingly recognized as a neuroinflammatory condition characterized by dysregulated cytokine networks. This comprehensive review examines the immunomodulatory effects of antidepressant medications, revealing their significant impact on Th1/Th2 cytokine balance beyond their classical neurotransmitter actions. Clinical data show that diverse antidepressant classes consistently demonstrate immunomodulatory properties that extend beyond their classical neurotransmitter effects. These medications reduce pro-inflammatory markers (IFN-γ, TNF-α, IL-6) while enhancing anti-inflammatory cytokines (IL-10, TGF-β), effects particularly relevant for treatment-resistant cases with elevated baseline inflammation. The therapeutic potential of these immunoregulatory effects is supported by emerging interventions, including low-dose IL-2 immunotherapy, vagus nerve stimulation, and microbiota-targeted therapies, which show promise for specific depression subtypes. Importantly, these approaches appear most effective when guided by inflammatory biomarkers, suggesting a path toward personalized treatment strategies. By integrating findings from clinical studies and translational research, this work establishes immune modulation as a fundamental component of antidepressant action. The review provides a framework for developing next-generation treatments that target neuroimmune pathways in MDD, with particular emphasis on practical applications for treatment-resistant cases. These insights bridge the gap between neuropharmacology and clinical psychiatry, offering new therapeutic possibilities for patients with inflammation-associated depression.