Germinal centers (GCs) are anatomic sites where B cells undergo secondary diversification to produce high-affinity, class-switched Abs. We hypothesized that proliferating B cells in GCs create a hypoxic microenvironment that governs their further differentiation. Using molecular markers, we found GCs to be predominantly hypoxic. Compared to normoxia (21% O₂), hypoxic culture conditions (1% O₂) in vitro accelerated class switching and plasma cell formation and enhanced expression of GL-7 on B and CD4⁺ T cells. Reversal of GC hypoxia in vivo by breathing 60% O₂ during immunization resulted in reduced frequencies of GC B cells, T follicular helper cells, and plasmacytes, as well as lower expression of ICOS on T follicular helper cells. Importantly, this reversal of GC hypoxia decreased Ag-specific serum IgG1 and reduced the frequency of IgG1⁺ B cells within the Ag-specific GC. Taken together, these observations reveal a critical role for hypoxia in GC B cell differentiation.

Aim. This paper reports a systematic review and critical appraisal of the evidence on the effectiveness of behavioral therapies such as yoga and mindfulness practices for stroke rehabilitation.Background. The experience of stroke can have a negative impact on both psychological and physical health and on quality of life. Yoga and relevant practices are promising therapies that have been used with patients with a variety of conditions. In order to draw conclusions on effectiveness for stroke patients, the evidence requires systematic assessment.Methods. A comprehensive search of major biomedical and complementary medicine databases was conducted. Relevant research was categorized by study type and appraised according to study design.Results. Five randomized controlled clinical trials and four single case studies were found. Additionally, one qualitative research study was identified. Studies reported positive results, including improvements in cognition, mood, and balance and reductions in stress. Modifications to different yoga practices make comparison between studies difficult, and a lack of controlled studies precludes any firm conclusions on efficacy.Conclusion. Yoga and mindfulness could be clinically valuable self-administered intervention options for stroke rehabilitation. Further research is needed to evaluate these specific practices and their suitability in stroke rehabilitation.

Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent.

Potassium ions (K⁺) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K⁺ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K⁺ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K⁺ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K⁺ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K⁺ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs’ immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K⁺ ion-rich TME, which has important implications for MDSCs-targeted therapies.

G protein–coupled receptor 84 (GPR84) is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T-cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T-cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacologic antagonism with GLPG1205 or genetic deletion of GPR84 promoted T-cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T-cell function and may further enhance adoptive cellular therapies.