Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.

Intravenous infusion has been used as the method of cell delivery in many preclinical studies as well as in some early clinical trials. Among its advantages are broad distribution, ability to handle a large-volume infusion, and ease of access. Progenitor cells used in cell-based therapy act through their secretomes, rather than their ability to differentiate into lineage-specific cell type. Since not all progenitor cells have similar secretome potency, the innate abilities of the secretome of cells used in clinical trials will obviously dictate their effectiveness. We previously found that cardiac neonatal mesenchymal stromal cells (nMSCs) are more effective in repairing the infarcted myocardium compared to adult mesenchymal stromal cells (aMSCs) due to their robust secretome (Sharma et al Circulation Research 120:816-834, 2017). In this study, we explored the efficacy of intravenous (IV) delivery of nMSCs for myocardial recovery. Six-week-old male Brown Norway rats underwent acute MI by ligation of the left anterior descending artery, followed by IV infusion of cell dose 5 × 106 nMSCs/rat body weight (kg) or saline on days 0 and 5. We found that cardiac parameters in the rodent ischemia model improved 1 month after nMSCs infusion, and the result is comparable with the intramyocardial injection of nMSCs. Tracking the infused cells in target organ revealed that their movement after IV delivery was mediated by the cell surface receptor CD44. Systemic injection of nMSCs stimulated immunomodulatory responses specifically by increasing FoxP3+ T-regulatory cell influenced anti-inflammatory macrophages (M2) in heart. These data demonstrate that nMSCs promote immunogenic tolerance via CD44-driven T-reg/M2 stimulation that helps nMSCs for longer viability in the injured myocardium for better functional recovery. Our data also demonstrate a rationale for a clinical trial of IV infusion of nMSCs to promote cardiac function improvement in the ischemic patients.
© 2024. The Author(s).

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases.
© 2022. The Author(s).

Aim: To assess the effect of physical training on the selected parameters of the immune system regarding CD3, CD4, CD8, CD11, CD161, CD45A cell counts in rats treated with N-methyl-N-nitrosourea (MNU). Material and Methods: Thirty-eight female Sprague-Dawley rats were injected intraperitoneally with MNU and were divided into three groups, i.e., sedentary control (SC), the group of moderate-intensity training (MIT) and the group of high-intensity training (HIT). Physical training was supervised immediately after MNU administration and was conducted 5 days per week for 12 weeks on a three-position treadmill. Results: A significant difference was found between SC and training groups in terms of the number of induced tumors per rat (1.57 vs. 0.4, p = 0.05) and in the following lymphocyte subpopulations: CD4+/CD8+ (p = 0.01), CD3−/CD11b+ (p = 0.02), CD3−/CD161+ (p = 0.002), CD3−/CD161− (p = 0.002), CD3+/CD45RA+ (p = 0.003) and CD3−/CD45RA+ (p = 0.005). In terms of the intensity of physical training, the highest efficacy was found for MIT and the following lymphocyte subpopulations: CD3−/CD11b+ (SC vs. MIT, p < 0.001), CD3−/CD161+ (SC vs. MIT, p = 0.002), CD3−/CD161− (SC vs. MIT, p = 0.002), CD3+/CD45RA+ (SC vs. MIT, p = 0.02) and CD3−/CD45RA+ (SC vs. MIT, p < 0.001, MIT vs. HIT, p = 0.02). Furthermore, negative correlations were found between the number of apoptotic cells and CD3−/CD11b (r = −0.76, p = 0.01) in SC and between the number of induced tumors and CD3+/CD8+ (r = −0.61, p = 0.02) and between their volume and CD+/CD8+ (r = −0.56, p = 0.03) in the group of rats undergoing training. Conclusions: Physical training, particularly MIT, affected immune cell function and an altered immune response can be considered a mechanism underlying the effect of exercise on breast cancer development.

Lung dendritic cells (DC) are powerful antigen-presenting cells constituted by various subpopulations that differ in terms of their function and origin and differentially regulate cell-mediated antifungal immunity. The lung is the primary target organ of Cryptococcus neoformans and C. gattii infections, which makes it essential in the establishment of the first line of anti-cryptococcal defense. However, the lung-specific dynamics and function of DC subsets are poorly understood in cryptococcosis. In this study, we provide evidence for the in vivo function of a conventional langerin-expressing DC1 dendritic cell (LangDC1) population during the first week of intratracheal C. neoformans infection in mice. By using conditional depletion of LangDC1 after diphtheria toxin treatment of LangDTREGFP mice, we demonstrate that these animals better control the fungal infection and produce type 1 and 17 cytokines in the context of a type 2 immune response, favoring a predominance of iNOS over arginase-1 expression by pulmonary cells. Our results suggest that LangDC1 cells play a role in impairing immune response for the clearance of C. neoformans in the early stage of pulmonary infection.