Summary The CD8+ memory T cell population is heterogeneous and it is unclear which subset(s) optimally mediate the central goal of the immune system-protection against infection. Here we investigate the protective capacities of CD8+ T cell subsets present at the memory stage of the immune response. We show that a population of CD8+ T cells bearing markers associated with effector cells (KLRG1hi, CD27lo, T-bethi, Eomeslo) persisted to the memory phase and provided optimal control of Listeria monocytogenes and vaccinia virus, despite weak recall proliferative responses. After antigen specific boosting, this population formed the predominant secondary memory subset, and maintained superior pathogen control. The effector-like memory subset displayed a distinct pattern of tissue distribution and localization within the spleen, and their enhanced capacity to eliminate Listeria involved specialized utilization of cytolysis. Together these data suggest “long-lived effector” CD8+ T cells are optimal for protective immunity against certain pathogens.

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Summary Background Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases. Objective We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs. Methods We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m3) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced. Results We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P < 0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P < 0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hr to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis. Conclusions and Clinical Relevance Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.

Although major advances have been made in hematopoietic stem cell transplantation (HSCT) and solid organ transplantation in the last 50 years, big challenges remain. This Review outlines the current immunological limitations for HSCT and solid organ transplantation, and discusses new immune-modulating therapies in clinical trials and under pre-clinical development that may allow these obstacles to be overcome.

Key Points• IL-2/mAb complexes expand Tregs and treat established murine cGVHD, but concurrent T-effector cell expansion can reduce their therapeutic index.• Prophylactic Treg infusions can prevent cGVHD, whereas therapeutic efficacy requires homing to and inhibition of the GC reaction.Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. (Blood. 2016;128(7):1013-1017