Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

T cell co-signaling molecules play an important role in fine-tuning the strength of T cell activation during many types of immune responses, including infection, cancer, transplant rejection, and autoimmunity. Over the last few decades, intense research into these cosignaling molecules has provided rich evidence to suggest that cosignaling molecules may be harnessed for the treatment of immune-related diseases. In particular, coinhibitory molecules such as programmed-death 1, 2B4, BTLA, TIGIT, LAG-3, TIM-3, and CTLA-4 inhibit T cell responses by counteracting TCR and costimulatory signals, leading to the inhibition of proliferation and effector function and the downregulation of activation and adhesion molecules at the cell surface. While many reviews have focused on the role of coinhibitory molecules in modifying primary CD8+ T cell responses, in this review, we will consider the complex role of coinhibitory molecules in altering CD8+ T cell recall potential. As memory CD8+ T cell responses are critical for protective memory responses in infection and cancer and contribute to potentially pathogenic memory responses in transplant rejection and autoimmunity, understanding the role of coinhibitory receptor control of memory T cells may illuminate important aspects of therapeutically targeting these pathways

Data_Sheet_1_Survival and reproduction in Arctic caribou are associated with summer forage and insect harassment.docx

Investigators have speculated that the climate-driven “greening of the Arctic” may benefit barren-ground caribou populations, but paradoxically many populations have declined in recent years. This pattern has raised concerns about the influence of summer habitat conditions on caribou demographic rates, and how populations may be impacted in the future. The short Arctic summer provides caribou with important forage resources but is also the time they are exposed to intense harassment by insects, factors which are both being altered by longer, warmer growing seasons. To better understand the effects of summer forage and insect activity on Arctic caribou demographic rates, we investigated the influence of estimated forage biomass, digestible energy (DE), digestible nitrogen (DN), and mosquito activity on the reproductive success and survival of adult females in the Central Arctic Herd on the North Slope of Alaska. We tested the hypotheses that greater early summer DN would increase subsequent reproduction (parturition and late June calving success) while greater biomass and DE would increase adult survival (September–May), and that elevated mosquito activity would reduce both demographic rates. Because the period when abundant forage DN is limited and overlaps with the period of mosquito harassment, we also expected years with low DN and high harassment to synergistically reduce caribou reproductive success. Examining these relationships at the individual-level, using GPS-collared females, and at the population-level, using long-term monitoring data, we generally found support for our expectations. Greater early summer DN was associated with increased subsequent calving success, while greater summer biomass was associated with increased adult survival. Mosquito activity was associated with reductions in adult female parturition, late June calving success, and survival, and in years with low DN, had compounding effects on subsequent late June calving success. Our findings indicate that summer nutrition and mosquito activity collectively influence the demographic rates of Arctic caribou, and may impact the dynamics of populations in the future under changing environmental conditions.</p

Signaling through the inhibitory Fc receptor Fc gamma RIIB Induces CD8+ T Cell apoptosis to limit T Cell immunity

Effector CD8+ T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8+ T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8+ T cell-intrinsic genetic deletion of Fcgr2b increased CD8+ effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcγRIIB in regulating CD8+ T cell immunity

Novel insights into serodiagnosis and epidemiology of Erysipelothrix rhusiopathiae, a newly recognized pathogen in muskoxen (Ovibos moschatus).

BackgroundMuskoxen are a key species of Arctic ecosystems and are important for food security and socio-economic well-being of many Indigenous communities in the Arctic and Subarctic. Between 2009 and 2014, the bacterium Erysipelothrix rhusiopathiae was isolated for the first time in this species in association with multiple mortality events in Canada and Alaska, raising questions regarding the spatiotemporal occurrence of the pathogen and its potential impact on muskox populations.Materials and methodsWe adapted a commercial porcine E. rhusiopathiae enzyme-linked immunosorbent assay to test 958 blood samples that were collected from muskoxen from seven regions in Alaska and the Canadian Arctic between 1976 and 2017. The cut-off between negative and positive results was established using mixture-distribution analysis, a data-driven approach. Based on 818 samples for which a serological status could be determined and with complete information, we calculated trends in sample seroprevalences in population time-series and compared them with population trends in the investigated regions.ResultsOverall, 219/818 (27.8%, 95% Confidence Interval: 24.7-31.0) samples were classified as positive for exposure to E. rhusiopathiae. There were large variations between years and regions. Seropositive animals were found among the earliest serum samples tested; 1976 in Alaska and 1991 in Canada. In Alaskan muskoxen, sample seroprevalence increased after 2000 and, in two regions, peak seroprevalences occurred simultaneously with population declines. In one of these regions, concurrent unusual mortalities were observed and E. rhusiopathiae was isolated from muskox carcasses. In Canada, there was an increase in sample seroprevalence in two muskox populations following known mortality events that had been attributed to E. rhusiopathiae.ConclusionOur results indicate widespread exposure of muskoxen to E. rhusiopathiae in western Canada and Alaska. Although not new to the Arctic, we documented an increased exposure to the pathogen in several regions concurrent with population declines. Understanding causes for the apparent increased occurrence of this pathogen and its association with large scale mortality events for muskoxen is critical to evaluate the implications for wildlife and wildlife-dependent human populations in the Arctic