Splenocyte transfer from hypertensive donors eliminates premenopausal female protection from Ang II-induced hypertension

Premenopausal females are protected from Angiotensin II (Ang II)-induced hypertension following the adoptive transfer of T cells from normotensive donors. For the present study, we hypothesized that the transfer of hypertensive T cells (HT) or splenocytes (HS) from hypertensive donors would eliminate premenopausal protection from hypertension. Premenopausal Rag-1-/- females received either normotensive (NT) or hypertensive cells, three weeks prior to Ang II infusion (14 days, 490 ng/kg/min). Contrary to our hypothesis, no increase in Ang II-induced blood pressure was observed in the NT/Ang or HT/Ang groups. Flow cytometry demonstrated that renal FoxP3+ T regulatory cells were significantly decreased and IHC showed an increase in renal F4/80+ macrophages in HT/Ang, suggesting a shift in the renal inflammatory environment despite no change in blood pressure. Renal mRNA expression of MCP-1, Endothelin-1, GPER-1 were significantly decreased in HT/Ang. The adoptive transfer of hypertensive splenocytes prior to Ang II infusion (HS/Ang) eliminated premenopausal protection from hypertension and significantly decreased splenic FoxP3+ T regulatory cells compared to females receiving normotensive splenocytes (NS/Ang). Expression of MIP-1a/CCL3, a potent macrophage chemokine was elevated in HS/Ang, however no increase in renal macrophage infiltration occurred. Together, these data show that in premenopausal females T cells from hypertensive donors are not sufficient to induce a robust Ang II mediated hypertension, in contrast, transfer of hypertensive splenocytes (consisting of T/B lymphocytes, dendritic cells, macrophages) is sufficient. Further work is needed to understand how innate and adaptive immune cells and estrogen signaling coordinate to cause differential hypertensive outcomes in premenopausal females.

Sociodemographic effects on immune cell composition in a free-ranging non-human primate

Aging results in declines in immune function and increases in inflammation, which underlie many age-related diseases. These immunosenescent signatures are similar to those seen in individuals exposed to social adversity, who may age more rapidly than those unexposed. Yet, it is unclear how social adversity alters immunity across demographic factors - data that are essential to identify how it might increase aging-related diseases. Here, we investigated how age, sex, and social adversity predicted immune cell proportions in 250 rhesus macaques living in a semi-naturalistic colony. As macaques aged, they exhibited signatures of immunosenescence. Older individuals had signatures of diminished antibody production and adaptive immunity, with declines in CD20+ B cells, CD20+/CD3+ cell ratio, and the CD4+/CD8+ T cell ratio. At all ages, females had higher CD20+/CD3+ and CD4+/CD8+ ratios, indicative of a stronger antibody and adaptive immune response that may facilitate pathogen clearance even with increasing age. Older individuals had signatures of inflammation, with higher proportions of CD3+/CD8+ Cytotoxic T cells, CD16+/CD3- Natural Killer cells, CD3+/CD4+/CD25+ and CD3+/CD8+/CD25+ T regulatory cells, and CD14+/CD16+/HLA-DR+ intermediate monocytes, combined with lower levels of CD14+/CD16-/HLA-DR+ classical monocytes. Notably, we found an interaction between age and social adversity, where low-status individuals had higher proportions of CD3+/CD4+/CD25+ T regulatory cells for their age, compared to higher-status individuals. Together, our study identifies immune cell types that are affected by age and sex in the premier nonhuman primate model of human biology and behavior, and demonstrate a novel link between inflammatory CD4+ T regulatory cells and social adversity.

Metabolic and Anti-Inflammatory Effects of Antidepressants in Patients Diagnosed with Major Depressive Disorder: A Prospective Cohort Study

Introduction: There is growing evidence showing a correlation between major depression disorder (MDD), metabolic syndrome and inflammation. To examine the influence of antidepressant medications on the metabolic, inflammatory profiles, oxidative stress and endothelial derangement of patients suffering from MDD. Results Depressive patients displayed significantly higher serum triglycerides than control group, which increased significantly during eight weeks of antidepressive treatment. In the patients' group, serum levels of ALT and AST increased significantly during treatment. Serum peroxide level was significantly higher in patients before and during treatment vs. controls and decreased significantly in the patients' group during treatment. Macrophage chemoattractant protein-1 and hs-CRP serum levels were higher in patients before treatment as compared with controls. The percentage of gated IgM CD19+ and CD14+ cells in depressive patients before treatment was significantly higher than in the control group. The percentage of T regulatory cells increased significantly during antidepressive treatment. Discussion MDD patients had increased oxidative stress, inflammatory responses, metabolic derangements and endothelial injury. Antidepressant medications increased the percentage of T regulatory cells. Methods Twenty-nine patients aged 22-58 who were diagnosed with MDD but not medicated, were selected for the study. During the 8-week duration of the research, patients received anti-depressant medication.

Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor

CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts’ CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.

Platelets in ITP: Victims in Charge of Their Own Fate?

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakaryopoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned.

FoxP3 associates with enhancer-promoter loops to regulate Treg-specific gene expression

Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPL). T regulatory cells (Treg) identity is dominantly specified by the transcription factor FoxP3, whose mechanism of action is unclear. We applied proximity-ligation with chromatin immunoprecipitation (HiChIP) in Treg and closely related conventional CD4+ T cells (Tconv). EPL identified by H3K27Ac HiChIP showed a range of connection intensity, with some super-connected genes. TF-specific HiChIP showed that FoxP3 interacts with EPLs at a large number of genes, including some not differentially expressed in Treg vs Tconv, but enriched at the core Treg signature loci that it upregulates. FoxP3 association correlates with heightened H3H27Ac looping, as ascertained by analysis of FoxP3-deficient Treg-like cells. There was marked asymmetry in the loci where FoxP3 associated at the enhancer- or the promoter-side of EPLs, with enrichment for different transcriptional cofactors. FoxP3 EPL intensity distinguished gene clusters identified by single-cell ATAC-seq as co-varying between individual Tregs, supporting a direct transactivation model for FoxP3 in determining Treg identity.