Publisher Correction: Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

Acquired Clinical Immunity to Malaria in Nonhuman Primates Coinfected with Schistosoma and Plasmodium Parasites.

Naturally acquired immunity to malaria develops over several years and can be compromised by concomitant infections. This study explored the influence of chronic schistosomiasis on clinical outcome and immunity to repeated malaria infection. Two groups of baboons (n = 8 each), were infected with Schistosoma mansoni cercariae to establish chronic infections. One of the two groups was treated with praziquantel (PZQ) to eliminate schistosome infection. The two groups plus a new malaria control group (n = 8) were inoculated three times with Plasmodium knowlesi parasites at 1-month intervals. Clinical data and IgG, IgG1, memory T-cell, and monocyte levels were recorded. After three P. knowlesi infections, we observed (i) reduced clinical symptoms in all groups with each subsequent infection, (ii) increased IgG and IgG1 levels in the malaria control (Pk-only) group, (iii) increased IgG, IgG1, CD14+, and CD14- CD16+ levels in the Schistosoma-treated (Schisto/PZQ+Pk) group, and (iv) significantly lower IgG and IgG1 levels compared to those of the Pk-only group, reduced CD4+ CD45RO+ levels, and increased levels of CD14- CD16+ cells in the coinfected (Schisto+Pk) group. Chronic S. mansoni infection does not compromise establishment of clinical immunity after multiple malaria infections, with nonclassical monocytes seeming to play a role. Failure to develop robust antibody and memory T cells may have a long-term impact on acquired immunity to malaria infection.

Topical microbicides for preventing sexually transmitted infections.

BACKGROUND: This is a updated version of our Cochrane Review published in Issue 6, 2012. Sexually-transmitted infections (STIs) continue to rise worldwide, imposing an enormous morbidity and mortality burden. Effective prevention strategies, including microbicides, are needed to achieve the goals of the World Heath Organization (WHO) global strategy for the prevention and control of these infections. OBJECTIVES: To determine the effectiveness and safety of topical microbicides for preventing acquisition of STIs, including HIV. SEARCH METHODS: We undertook a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CLIB, Web of Science, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and reference lists of relevant articles up to August 2020. In addition, we contacted relevant organisations and experts. SELECTION CRITERIA: We included randomised controlled trials of vaginal microbicides compared to placebo (except for nonoxynol-9 because it is covered in related Cochrane Reviews). Eligible participants were sexually-active non-pregnant, WSM and MSM, who had no laboratory confirmed STIs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies, extracted data, and assessed risks of bias in duplicate, resolving differences by consensus. We conducted a fixed-effect meta-analysis, stratified by type of microbicide, and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included eight trials from the earlier version of the review and four new trials, i.e. a total of 12 trials with 32,464 participants (all WSM). We did not find any eligible study that enrolled MSM or reported fungal STI as an outcome. We have no study awaiting assessment. All 12 trials were conducted in sub-Saharan Africa, with one having a study site in the USA, and another having a site in India. Vaginal microbicides tested were BufferGel and PRO 2000 (1 trial, 3101 women), Carraguard (1 trial, 6202 women), cellulose sulphate (2 trials, 3069 women), dapivirine (2 trials, 4588 women), PRO 2000 (1 trial, 9385 women), C31G (SAVVY) (2 trials, 4295 women), and tenofovir (3 trials, 4958 women). All microbicides were compared to placebo and all trials had low risk of bias. Dapivirine probably reduces the risk of acquiring HIV infection: risk ratio (RR) 0.71, (95% confidence interval (CI) 0.57 to 0.89, I2 = 0%, 2 trials, 4588 women; moderate-certainty evidence). The other microbicides may result in little to no difference in the risk of acquiring HIV (low-certainty evidence); including tenofovir (RR 0.83, 95% CI 0.68 to 1.02, cellulose sulphate (RR 1.20, 95% CI 0.74 to 1.95, BufferGel (RR 1.05, 95% CI 0.73 to 1.52), Carraguard (RR 0.89, 95% CI 0.71 to 1.11), PRO 2000 (RR 0.93, 95% CI 0.77 to 1.14), and SAVVY (RR 1.38, 95% CI 0.79 to 2.41). Existing evidence suggests that cellulose sulphate (RR 0.99, 95% CI 0.37 to 2.62, 1 trial, 1425 women), and PRO 2000 (RR 0.95, 95% CI 0.73 to 1.23) may result in little to no difference in the risk of getting herpes simplex virus type 2 infection (low-certainty evidence). Two studies reported data on tenofovir's effect on this virus. One suggested that tenofovir may reduce the risk (RR 0.55, 95% CI 0.36 to 0.82; 224 participants) while the other did not find evidence of an effect (RR 0.94, 95% CI 0.85 to 1.03; 1003 participants). We have not reported the pooled result because of substantial heterogeneity of effect between the two studies (l2 = 85%). The evidence also suggests that dapivirine (RR 1.70, 95% CI 0.63 to 4.59), tenofovir (RR 1.27, 95% CI 0.58 to 2.78), cellulose sulphate (RR 0.69, 95% CI 0.26 to 1.81), and (Carraguard (RR 1.07, 95% CI 0.75 to 1.52) may have little or no effect on the risk of acquiring syphilis (low-certainty evidence). In addition, dapivirine (RR 0.97, 95% CI 0.89 to 1.07), tenofovir (RR 0.90, 95% CI 0.71 to 1.13), cellulose sulphate (RR 0.70, 95% CI 0.49 to 0.99), BufferGel (RR 0.97, 95% CI 0.65 to 1.45), Carraguard (RR 0.96, 95% CI 0.83 to 1.12), and PRO 2000 (RR 1.01, 95% CI 0.84 to 1.22) may result in little to no difference in the risk of acquiring chlamydia infection (low-certainty evidence). The evidence also suggests that current topical microbicides may not have an effect on the risk of acquiring gonorrhoea, condyloma acuminatum, trichomoniasis, or human papillomavirus infection (low-certainty evidence). Microbicide use in the 12 trials, compared to placebo, did not lead to any difference in adverse event rates. No study reported on acceptability of the intervention.  AUTHORS' CONCLUSIONS: Current evidence shows that vaginal dapivirine microbicide probably reduces HIV acquisition in women who have sex with men. Other types of vaginal microbicides have not shown evidence of an effect on acquisition of STIs, including HIV. Further research should continue on the development and testing of new microbicides.

Diagnosis of schistosomiasis mansoni: an evaluation of existing methods and research towards single worm pair detection.

The inadequacy of current diagnostics for the detection of low worm burdens in humans means that schistosomiasis mansoni is more widespread than previously acknowledged. With the inception of mass drug treatment programmes aimed at disease elimination and the advent of human vaccine trials, the need for more sensitive diagnostics is evident. In this review, we evaluate the merits and limitations of the principal diagnostic methods, namely detection of eggs in faeces; anti-schistosome antibodies in serum; parasite-derived proteins and glycans in serum or urine; parasite DNA in blood, faeces or urine. Only in the baboon model, where actual worm burden is determined by portal perfusion, have faecal smear and circulating antigen methods been calibrated, and shown to have thresholds of detection of 10-19 worm pairs. There is scope for improvement in all the four methods of detection, e.g. the identification of single targets for host antibodies to improve the specificity of enzyme linked immunosorbent assay. Despite recent advances in the definition of the schistosome secretome, there have been no comprehensive biomarker investigations of parasite products in the urine of infected patients. Certainly, the admirable goal of eliminating schistosomiasis will not be achieved unless individuals with low worm burdens can be diagnosed.

High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL17 against M. tuberculosis antigen.

Background: Interleukin 17 producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with Human Immunodeficiency Virus (HIV) disproportionately affects distinct Th17 cell subsets that respond to Mtb is incompletely defined. Methods: We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by LC/MS on plasma and tested the hypothesis that tryptophan catabolism influences Th17 cell frequencies in this context. Results: We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+ and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3- cells of which subset 1 was significantly reduced in LTBI with HIV-ART, yet Mtb-responsive IL17-producing CD4 T cells were preserved; we found that IL17-producing CD4 T cells dominate the response to Mtb antigen but not CMV antigen or staphylococcal enterotoxin B (SEB); and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17 cell frequencies. Conclusions: We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL-17 against M. tuberculosis antigen.

Background: Interleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined. Methods: We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context. Results: We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies. Conclusions: We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and functional roles.

B cells are important in tuberculosis (TB) immunity, but their role in the human lung is understudied. Here, we characterize B cells from lung tissue and matched blood of patients with TB and found they are decreased in the blood and increased in the lungs, consistent with recruitment to infected tissue, where they are located in granuloma associated lymphoid tissue. Flow cytometry and transcriptomics identify multiple B cell populations in the lung, including those associated with tissue resident memory, germinal centers, antibody secretion, proinflammatory atypical B cells, and regulatory B cells, some of which are expanded in TB disease. Additionally, TB lungs contain high levels of Mtb-reactive antibodies, specifically IgM, which promotes Mtb phagocytosis. Overall, these data reveal the presence of functionally diverse B cell subsets in the lungs of patients with TB and suggest several potential localized roles that may represent a target for interventions to promote immunity or mitigate immunopathology.

Rare Variable M. tuberculosis Antigens induce predominant Th17 responses in human infection.

CD4 T cells are essential for immunity to M. tuberculosis (Mtb), and emerging evidence indicates that IL-17-producing Th17 cells contribute to immunity to Mtb. While identifying protective T cell effector functions is important for TB vaccine design, T cell antigen specificity is also likely to be important. To identify antigens that induce protective immunity, we reasoned that as in other pathogens, effective immune recognition drives sequence diversity in individual Mtb antigens. We previously identified Mtb genes under evolutionary diversifying selection pressure whose products we term Rare Variable Mtb Antigens (RVMA). Here, in two distinct human cohorts with recent exposure to TB, we found that RVMA preferentially induce CD4 T cells that express RoRγt and produce IL-17, in contrast to 'classical' Mtb antigens that induce T cells that produce IFNγ. Our results suggest that RVMA can be valuable antigens in vaccines for those already infected with Mtb to amplify existing antigen-specific Th17 responses to prevent TB disease.

The Road to Elimination: Current State of Schistosomiasis Research and Progress Towards the End Game.

The new WHO Roadmap for Neglected Tropical Diseases targets the global elimination of schistosomiasis as a public health problem. To date, control strategies have focused on effective diagnostics, mass drug administration, complementary and integrative public health interventions. Non-mammalian intermediate hosts and other vertebrates promote transmission of schistosomiasis and have been utilized as experimental model systems. Experimental animal models that recapitulate schistosomiasis immunology, disease progression, and pathology observed in humans are important in testing and validation of control interventions. We discuss the pivotal value of these models in contributing to elimination of schistosomiasis. Treatment of schistosomiasis relies heavily on mass drug administration of praziquantel whose efficacy is comprised due to re-infections and experimental systems have revealed the inability to kill juvenile schistosomes. In terms of diagnosis, nonhuman primate models have demonstrated the low sensitivity of the gold standard Kato Katz smear technique. Antibody assays are valuable tools for evaluating efficacy of candidate vaccines, and sera from graded infection experiments are useful for evaluating diagnostic sensitivity of different targets. Lastly, the presence of Schistosomes can compromise the efficacy of vaccines to other infectious diseases and its elimination will benefit control programs of the other diseases. As the focus moves towards schistosomiasis elimination, it will be critical to integrate treatment, diagnostics, novel research tools such as sequencing, improved understanding of disease pathogenesis and utilization of experimental models to assist with evaluating performance of new approaches.

Performance Evaluation of Lateral Flow Assays for Coronavirus Disease-19 Serology.

The coronavirus disease of 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has undoubtedly resulted in significant morbidities, mortalities, and economic disruptions across the globe. Affordable and scalable tools to monitor the transmission dynamics of the SARS-CoV-2 virus and the longevity of induced antibodies will be paramount to monitor and control the pandemic as multiple waves continue to rage in many countries. Serologic assays detect humoral responses to the virus, to determine seroprevalence in target populations, or induction of antibodies at the individual level following either natural infection or vaccination. With multiple vaccines rolling out globally, serologic assays to detect anti-SARS-CoV-2 antibodies will be important tools to monitor the development of herd immunity. To address this need, serologic lateral flow assays (LFAs), which can be easily implemented for both population surveillance and home use, will be vital to monitor the evolution of the pandemic and inform containment measures. Such assays are particularly important for monitoring the transmission dynamics and durability of immunity generated by natural infections and vaccination, particularly in resource-limited settings. In this review, we discuss considerations for evaluating the accuracy of these LFAs, their suitability for different use cases, and implementation opportunities.

Do vaginal microbicides reduce the risk of HIV acquisition in women?

Currently, no single HIV prevention method meets the needs of all people at risk of infection and a range of options are needed for individuals to protect themselves and to curb the HIV epidemic. Many people living with HIV or at risk for HIV infection in low and middle-income countries do not have access to prevention, treatment and care, and there is still no cure. Despite large preventive efforts, HIV acquisition rates remain unacceptably high and transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Widespread violence, many sociocultural and economic factors in these regions limit the ability of women to insist on safer sexual practices to decrease HIV transmission risks. The development of vaginal HIV microbicides, the use of which would be discretely controlled or initiated by women, has therefore attracted much interest as a strategy to help prevent HIV sexual transmission. In this commentary, we discuss the evolution of vaginal microbicies, the different types that have undergone clinical trials, the past challenges to future hopes, the products that are currently in use and implications for women who are at risk to HIV infection in sub-Saharan Africa.

A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires.

Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous 'Clusters of Expanded TCRs (CETs)' can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.

Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung.

T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue-resident memory T cells (Trms) are superior at controlling many pathogens, including Mycobacterium tuberculosis (M. tuberculosis), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct CD4+ and CD8+ Trm-like clusters within TB-diseased lung tissue that were functional and enriched for IL-17-producing cells. M. tuberculosis-specific CD4+ T cells producing TNF-α, IL-2, and IL-17 were highly expanded in the lung compared with matched blood samples, in which IL-17+ cells were largely absent. Strikingly, the frequency of M. tuberculosis-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1ß levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and was associated with increased NO production. Taken together, these data support an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells in the immune control of M. tuberculosis in the human lung.

Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire.

Repeated Plasmodium falciparum infections drive the development of clinical immunity to malaria in humans; however, the immunological mechanisms that underpin this response are only partially understood. We investigated the impact of repeated P. falciparum infections on human γδ T cells in the context of natural infection in Malian children and adults, as well as serial controlled human malaria infection (CHMI) of U.S. adults, some of whom became clinically immune to malaria. In contrast to the predominant Vδ2+ T cell population in malaria-naïve Australian individuals, clonally expanded cytotoxic Vδ1effector T cells were enriched in the γδ T cell compartment of Malian subjects. Malaria-naïve U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the γδ T cell repertoire. Specifically, innate-like Vδ2+ T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas Vδ1+ T cells increased in frequency with repeated infections. Moreover, repeated P. falciparum infection drove waves of clonal selection in the Vδ1+ T cell receptor repertoire that coincided with the differentiation of Vδ1naïve T cells into cytotoxic Vδ1effector T cells. Vδ1+ T cells of malaria-exposed Malian and U.S. individuals were licensed for reactivity to P. falciparum parasites in vitro. Together, our study indicates that repeated P. falciparum infection drives the clonal expansion of an adaptive γδ T cell repertoire and establishes a role for Vδ1+ T cells in the human immune response to malaria.

Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs.

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and γδ T cells. We exploited the distinctive nature of DURTs and γδ T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCRδ repertoire, in contrast, was highly skewed in the lungs, where it was dominated by Vδ1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident γδ T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease.

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection.

The intestinal mucosa is enriched for unconventional T-cells, including mucosal associated invariant T-cells (MAIT), invariant natural killer T-cells (iNKT) and γδ T-cells. These cells are activated by bacterial metabolites, lipid antigens and cytokines, and are important for intestinal barrier integrity. The loss of gut homeostasis observed in HIV infection is central to disease pathogenesis, and studies have highlighted impairment of particular unconventional T-cell subsets within a specific gut compartment. However, although the small and large intestine are distinct niches, the overall impact of HIV on unconventional T-cells across the gut mucosal has not been well-studied. We hypothesized that compartment specific differences in the unconventional T-cell repertoire would exist between the small and large intestine, due to increasing bacterial loads and microbial diversity; and that the impact of HIV infection might differ depending on the compartment examined. We used mass cytometry, flow cytometry and unbiased T-cell receptor profiling to quantify unconventional T-cells in blood and tissue from the small (duodenum) and large (colon) intestine in HIV infected and uninfected participants undergoing examination for a range of intestinal conditions. Overall, we find distinct compartmentalisation of T-cells between blood, duodenum and colon, with iNKT cells significantly enriched in the duodenum and δ-1 expressing γδ T-cells in the colon. In addition, we observe greater clonal expansion of conventional TCRs in the duodenum, suggestive of stronger adaptive immunity in this compartment. Conversely, we find evidence of an expanded unconventional TCR repertoire in the colon, which contained far more overlapping "donor unrestricted" sequences than the duodenum. Twelve of these TCRs were highly "MAIT-like" and 3 were unique to the colon, suggesting an enrichment of donor unrestricted T-cells (DURTs) in this compartment. Unexpectedly, however, no significant impact of HIV infection on any of the unconventional T-cell subsets measured was observed in either mucosal site in terms of frequency or TCR repertoire. Further studies are required to investigate the importance of these unconventional T-cell subsets to intestinal homeostasis within the different gut compartments and determine if they are functionally impaired during HIV infection.

Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α.

Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.

Lung Tissue Resident Memory T-Cells in the Immune Response to Mycobacterium tuberculosis.

Despite widespread BCG vaccination and effective anti-TB drugs, Tuberculosis (TB) remains the leading cause of death from an infectious agent worldwide. Several recent publications give reasons to be optimistic about the possibility of a more effective vaccine, but the only full-scale clinical trial conducted failed to show protection above BCG. The immunogenicity of vaccines in humans is primarily evaluated by the systemic immune responses they generate, despite the fact that a correlation between these responses and protection from TB disease has not been demonstrated. A novel approach to tackling this problem is to study the local immune responses that occur at the site of TB infection in the human lung, rather than those detectable in blood. There is a growing understanding that pathogen specific T-cell immunity can be highly localized at the site of infection, due to the existence of tissue resident memory T-cells (Trm). Notably, these cells do not recirculate in the blood and thus may not be represented in studies of the systemic immune response. Here, we review the potential role of Trms as a component of the TB immune response and discuss how a better understanding of this response could be harnessed to improve TB vaccine efficacy.

Plasma IL-5 but Not CXCL13 Correlates With Neutralization Breadth in HIV-Infected Children.

Children may be the optimal target for HIV vaccine development as they generate substantially more frequent and more potent broadly HIV neutralizing antibodies (bnAbs) than adults. Development of a biomarker that correlates with neutralization breadth in this group could function as a powerful tool to facilitate the development of an HIV vaccine. Previously, we observed that this preferential ability in HIV-infected children over adults to generate bnAbs is associated with an enrichment of circulating follicular helper T-cells (TFH) with an effector phenotype, and the presence of IL-21 secreting HIV-specific TFH within lymphoid tissue germinal centers (GC). In adults, bnAbs development has been linked with high plasma levels of CXCL13, a chemoattractant for CXCR5-expressing TFH cells to the lymph node GC. We sought to test this relationship in HIV-infected children, but found no association between neutralization breadth and plasma levels of CXCL13, or with the Th2 cytokines IL-4 and IL-13, or the TFH associated factor Activin A. However, we did find an unexpected association between plasma IL-5 levels and bnAb development in these children. Importantly, although CXCL13 correlated with total circulating TFH cells, it was not associated with effector TFH. Additionally, raised CXCL13 expression was associated with a lower CD4 percentage, higher viral load and a loss of immune function, implying it is associated with progressive disease rather than HIV-specific GC activity in these subjects. Taken together, our data suggests that IL-5 should be evaluated further as a candidate plasma biomarker for HIV neutralization breadth and for monitoring vaccine responses in the pediatric age group.