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Central memory T (T CM ) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (T RM ) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated T RM cells rejoined the circulating pool. Epigenetic analyses revealed that T RM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated T RM cells isolated from small intestine epithelium exhibited the potential to differentiate into T CM cells, effector memory T cells and T RM cells on recall. Ex-T RM cells, former intestinal T RM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into T RM cells. Thus, T RM cells can rejoin the circulation but are advantaged to re-form local T RM when called on. Tissue-resident memory (T RM ) cells are generally stably maintained in discrete tissues or organs. Masopust and colleagues show that T RM cells can reenter the circulation, and exhibit considerable plasticity, although they retain a proclivity to reestablish themselves in their tissue of origin.

Tissue-resident memory T (T RM ) cells are non-recirculating cells that exist throughout the body. Although T RM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze T RM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T RM cell function, durability and malleability. We find that unequal responsiveness to TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103 − T RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-responsive CD103 + T RM counterparts. Furthermore, whereas CD103 − T RM cells readily modified their phenotype upon relocation, CD103 + T RM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for T RM cell development, tissue adaptation of these cells confers discrete functional properties such that T RM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment. Tissue-resident memory T (T RM ) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T RM cells are generated dictates their properties and is in turn defined according to T RM -cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

Tissue-resident memory T cells (TRM cells) provide rapid and superior control of localized infections. While the transcription factor Runx3 is a critical regulator of CD8+ T cell tissue residency, its expression is repressed in CD4+ T cells. Here, we show that, as a direct consequence of this Runx3-deficiency, CD4+ TRM cells lacked the transforming growth factor (TGF)-β-responsive transcriptional network that underpins the tissue residency of epithelial CD8+ TRM cells. While CD4+ TRM cell formation required Runx1, this, along with the modest expression of Runx3 in CD4+ TRM cells, was insufficient to engage the TGF-β-driven residency program. Ectopic expression of Runx3 in CD4+ T cells incited this TGF-β-transcriptional network to promote prolonged survival, decreased tissue egress, a microanatomical redistribution towards epithelial layers and enhanced effector functionality. Thus, our results reveal distinct programming of tissue residency in CD8+ and CD4+ TRM cell subsets that is attributable to divergent Runx3 activity.Mackay and colleagues show that distinct programs of tissue residency are induced in CD8+ and CD4+ TRM cell subsets, a difference attributable to the activity of the transcription factor Runx3.

Background Men who have sex with men (MSM) and transgender women (TGW) are disproportionately affected by HIV, with much higher incidence and prevalence rates than in the general population in different countries. There are several barriers to testing among MSM and TGW, such as low risk perception, anticipation of HIV-related stigma, discrimination of sexual orientation, in addition to difficulties related to care and access to health services. Therefore, analyzing the available evidence of the effectiveness of strategies for scaling up HIV testing among key populations is essential to point out potential knowledge gaps which may need to be addressed and develop public health policies to promote testing and early diagnosis of HIV infection. Methods An integrative review was carried out to evaluate strategies for scaling up HIV testing in these populations. Search strategy was performed on eight electronic databases, without language restriction. We included clinical trials, quasi-experimental studies, and non-randomized studies. Study selection and data extraction were both performed independently by pairs and disagreements were solved by a third revisor. The screening of the studies was carried out through the selection of titles/abstracts and the reading of the full texts of the pre-selected studies based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Data extraction was performed using a structured form. Results Thirty-seven publications referring to 35 studies were included, mostly being carried out in the United States of America and Australia. No studies were found evaluating disaggregated data on TGW. The studies were grouped into four types of intervention strategies: self-test distribution system (n = 10), organization of health services (n = 9), peer education (n = 6), and social marketing campaign (n = 10). Strategies that focused on the first three groups, combined or not, were more effective in increasing HIV testing among MSM. Conclusions Considering the diversity of interventions and the methodological heterogeneity of the included studies, strategies especially involving self-test distribution systems, associated with new information and communication technologies, should be evaluated in different communities and social contexts. Research evaluating specific studies on TGW population is still needed.

The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMΦs) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMΦs in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival.

Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.

Oral anticoagulation is the cornerstone treatment of several diseases. Its management is often challenging, and different telemedicine strategies have been implemented to support it. The aim of the study is to systematically review the evidence on the impact of telemedicine-based oral anticoagulation management compared to usual care on thromboembolic and bleeding events. Randomized controlled trials were searched in 5 databases from inception to September 2021. Two independent reviewers performed study selection and data extraction. Total thromboembolic events, major bleeding, mortality, and time in therapeutic range were assessed. Results were pooled using random effect models. In total, 25 randomized controlled trials were included (n=25,746 patients) and classified as moderate to high risk of bias by the Cochrane tool. Telemedicine resulted in lower rates of thromboembolic events, though not statistically significant (n=13 studies, relative risk [RR] 0.75, 95% CI 0.53-1.07; I =42%), comparable rates of major bleeding (n=11 studies, RR 0.94, 95% CI 0.82-1.07; I =0%) and mortality (n=12 studies, RR 0.96, 95% CI 0.78-1.20; I =11%), and an improved time in therapeutic range (n=16 studies, mean difference 3.38, 95% CI 1.12-5.65; I =90%). In the subgroup of the multitasking intervention, telemedicine resulted in an important reduction of thromboembolic events (RR 0.20, 95% CI 0.08-0.48). Telemedicine-based oral anticoagulation management resulted in similar rates of major bleeding and mortality, a trend for fewer thromboembolic events, and better anticoagulation quality compared to standard care. Given the potential benefits of telemedicine-based care, such as greater access to remote populations or people with ambulatory restrictions, these findings may encourage further implementation of eHealth strategies for anticoagulation management, particularly as part of multifaceted interventions for integrated care of chronic diseases. Meanwhile, researchers should develop higher-quality evidence focusing on hard clinical outcomes, cost-effectiveness, and quality of life. PROSPERO International Prospective Register of Systematic Reviews CRD42020159208; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=159208.

Over the past 20 years, the immune effector mechanisms involved in the control of Trypanosoma cruzi, as well as the receptors participating in parasite recognition by cells of the innate immune system, have been largely described. However, the main questions on the physiopathology of Chagas disease remain unanswered: “Why does the host immune system fail to provide sterile immunity?” and “Why do only a proportion of infected individuals develop chronic pathology?” In this review, we describe the mechanisms proposed to explain the inability of the immune system to eradicate the parasite and the elements that allow the development of chronic heart disease. Moreover, we discuss the possibility that the inability of infected cardiomyocytes to sense intracellular T. cruzi contributes to parasite persistence in the heart and the development of chronic pathology.

CD8 + T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8 + resident memory T cells (T RM cells) within the reproductive tracts of live female mice. We found that mucosal T RM cells were highly motile, but paused and underwent in situ division after local antigen challenge. T RM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent T RM cell differentiation in situ. However, the proliferation of pre-existing T RM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary T RM cell population. We observed similar results in skin. Thus, T RM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue. Masopust and colleagues show that mucosal tissue-resident memory T cells proliferate in situ in response to local antigen and dominate the local recall response.