Commitment to the T and natural killer T (NKT) cell lineages is determined during alphabeta T cell receptor (TCR)-mediated interactions of common precursors with ligand-expressing cells in the thymus. Whereas mainstream thymocyte precursors recognize major histocompatibility complex (MHC) ligands expressed by stromal cells, NKT cell precursors interact with CD1d ligands expressed by cortical thymocytes. Here, we demonstrated that such homotypic T-T interactions generated "second signals" mediated by the cooperative engagement of the homophilic receptors Slamf1 (SLAM) and Slamf6 (Ly108) and the downstream recruitment of the adaptor SLAM-associated protein (SAP) and the Src kinase Fyn, which are essential for the lineage expansion and differentiation of the NKT cell lineage. These receptor interactions were required during TCR engagement and therefore only occurred when selecting ligands were presented by thymocytes rather than epithelial cells, which do not express Slamf6 or Slamf1. Thus, the topography of NKT cell ligand recognition determines the availability of a cosignaling pathway that is essential for NKT cell lineage development.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to EpsteinBarr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A ؊/؊ mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A ؊/؊ mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A ؊/؊ B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A ؊/؊ mice with CD4 ؉ T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naïve SH2D1A ؊/؊ B cells became evident upon cotransfer with nonprimed wt CD4 ؉ cells into Rag2 ؊/؊ recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.Epstein-Barr virus ͉ germinal center ͉ immunoglobulin ͉ SLAM͞CD150

The expression of the new Ly108 isoform H1 weakens lupus-like disease of C57BL/6.Sle1b mice.

Ly108, a glycoprotein of the signaling lymphocytic activation molecule family of cell surface receptors expressed by T, B, NK, and APCs has been shown to have a role in NK cell cytotoxicity and T cell cytokine responses. In this study, we describe that CD4+ T cells from mice with a targeted disruption of exons 2 and 3 of Ly108 (Ly108ΔE2+3) produce significantly less IL-4 than wild-type CD4+ cells, as judged by in vitro assays and by in vivo responses to cutaneous infection with Leishmania mexicana. Surprisingly, neutrophil functions are controlled by Ly108. Ly108ΔE2+3 mice are highly susceptible to infection with Salmonella typhimurium, bactericidal activity of Ly108ΔE2+3 neutrophils is defective, and their production of IL-6, IL-12, and TNF-α is increased. The aberrant bactericidal activity by Ly108ΔE2+3 neutrophils is a consequence of severely reduced production of reactive oxygen species following phagocytosis of bacteria. Thus, Ly108 serves as a regulator of both innate and adaptive immune responses.

Objective To estimate the association between school attendance, school dropout, and risk of incident HIV and HSV-2 infection among young women. Design We used longitudinal data from a randomized controlled trial in rural Mpumalanga province, South Africa, to assess the association between school days attended, school dropout and incident HIV and HSV-2 in young women aged 13–23 years. Methods We examined inverse probability of exposure weighted survival curves and used them to calculate 1.5, 2.5 and 3.5-year risk differences and risk ratios for the effect of school attendance on incident HIV and HSV-2. A marginal structural Cox model was used to estimate hazard ratios for the effect of school attendance and school dropout on incident infection. Results Risk of infection increased over time as young women aged, and was higher in young women with low school attendance (<80% school days) compared to high (≥80% school days). Young women with low attendance were more likely to acquire HIV (HR: 2.97; 95% CI: 1.62, 5.45) and HSV-2 (HR: 2.47; 95% CI: 1.46,4.17) over the follow up period than young women with high attendance. Similarly, young women who dropped out of school had a higher weighted hazard of both HIV (HR 3.25 95% CI: 1.67,6.32) and HSV-2 (HR 2.70; 95% CI 1.59,4.59). Conclusion Young women who attend more school days and stay in school have a lower risk of incident HIV and HSV-2 infection. Interventions to increase frequency of school attendance and prevent dropout should be promoted to reduce risk of infection.

BackgroundHIV transmission can be decreased substantially by reducing the burden of undiagnosed HIV infection and expanding early and consistent use of antiretroviral therapy (ART). Treatment as prevention (TasP) has been proposed as key to ending the HIV epidemic. To activate TasP in high prevalence countries, like South Africa, communities must be motivated to know their status, engage in care, and remain in care. Community mobilization (CM) has the potential to significantly increase uptake testing, linkage to and retention in care by addressing the primary social barriers to engagement with HIV care—including poor understanding of HIV care; fear and stigma associated with infection, clinic attendance and disclosure; lack of social support; and gender norms that deter men from accessing care.Methods/designUsing a cluster randomized trial design, we are implementing a 3-year-theory-based CM intervention and comparing gains in HIV testing, linkage, and retention in care among individuals residing in 8 intervention communities to that of individuals residing in 7 control communities. Eligible communities include 15 villages within a health and demographic surveillance site (HDSS) in rural Mpumalanga, South Africa, that were not exposed to previous CM efforts. CM activities conducted in the 8 intervention villages map onto six mobilization domains that comprise the key components for community mobilization around HIV prevention. To evaluate the intervention, we will link a clinic-based electronic clinical tracking system in all area clinics to the HDSS longitudinal census data, thus creating an open, population-based cohort with over 30,000 18–49-year-old residents. We will estimate the marginal effect of the intervention on individual outcomes using generalized estimating equations. In addition, we will evaluate CM processes by conducting baseline and endline surveys among a random sample of 1200 community residents at each time point to monitor intervention exposure and community level change using validated measures of CM.DiscussionGiven the known importance of community social factors with regard to uptake of testing and HIV care, and the lack of rigorously evaluated community-level interventions effective in improving testing uptake, linkage and retention, the proposed study will yield much needed data to understand the potential of CM to improve the prevention and care cascade. Further, our work in developing a CM framework and domain measures will permit validation of a CM conceptual framework and process, which should prove valuable for community programming in Africa.Trial Registration NCT02197793 Registered July 21, 2014.

Background HIV and violence prevention programs increasingly seek to transform gender norms among participants, yet how to do so at the community level, and subsequent pathways to behavior change, remain poorly understood. We assessed shifts in endorsement of equitable gender norms, and intimate partner violence (IPV), during the three-year community-based trial of Tsima, an HIV 'treatment as prevention' intervention in rural South Africa. Methods Cross-sectional household surveys were conducted with men and women ages 18-49 years, in 8 intervention and 7 control communities, at 2014-baseline (n = 1,149) and 2018endline (n = 1,189). Endorsement of equitable gender norms was measured by the GEM Scale. Intent-to-treat analyses assessed intervention effects and change over time. Qualitative research with 59 community members and 38 staff examined the change process. Results Nearly two-thirds of men and half of women in intervention communities had heard of the intervention/seen the logo; half of these had attended a two-day workshop. Regression analyses showed a 15% improvement in GEM Scale score over time, irrespective of the intervention, among men (p<0.001) and women (p<0.001). Younger women (ages 18-29) had a decreased odds of reporting IPV in intervention vs. control communities (aOR 0.53;

How does the endorsement of different dimensions of gender norms by men and/or women influence their use of HIV testing and antiretroviral treatment? This question was examined using data from a 2014 population-based survey of 1053 women and 1004 men, ages 18–49, in rural South Africa. We used a global measure for views toward gender norms (the GEM Scale), plus four subsets of scale items (all reliabilities ≥ 0.7). In multivariate analyses using the global measure, endorsement of inequitable gender norms was associated with more testing (AOR 2.47, p < 0.01) and less treatment use (AOR 0.15, p < 0.01) among women but not men. When examining specific subsets of inequitable norms (e.g., endorsing men as the primary decision-maker), decreased odds of treatment use was found for men as well (AOR 0.18, p < 0.01). Careful attention to the role specific gender norms play in HIV service uptake can yield useful programmatic recommendations.