Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation.

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αß (LTαß) on Th17 cells and LTßR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTßR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.

Persistence of T Cell and Antibody Responses to SARS-CoV-2 Up to 9 Months after Symptom Onset.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces T cell, B cell, and Ab responses that are detected for several months in recovered individuals. Whether this response resembles a typical respiratory viral infection is a matter of debate. In this study, we followed T cell and Ab responses in 24 mainly nonhospitalized human subjects who had recovered from PCR-confirmed SARS-CoV-2 infection at two time points (median of 45 and 145 d after symptom onset). Ab responses were detected in 95% of subjects, with a strong correlation between plasma and salivary anti-spike (anti-S) and anti-receptor binding domain IgG, as well as a correlation between circulating T follicular helper cells and the SARS-CoV-2-specific IgG response. T cell responses to SARS-CoV-2 peptides were determined using intracellular cytokine staining, activation markers, proliferation, and cytokine secretion. All study subjects had a T cell response to at least one SARS-CoV-2 Ag based on at least one T cell assay. CD4+ responses were largely of the Th1 phenotype, but with a lower ratio of IFN-γ- to IL-2-producing cells and a lower frequency of CD8+:CD4+ T cells than in influenza A virus (IAV)-specific memory responses within the same subjects. Analysis of secreted molecules also revealed a lower ratio of IFN-γ to IL-2 and an altered cytotoxic profile for SARS-CoV-2 S- and nucleocapsid-specific responses compared with IAV-specific responses. These data suggest that the memory T cell phenotype after a single infection with SARS-CoV-2 persists over time, with an altered cytokine and cytotoxicity profile compared with long-term memory to whole IAV within the same subjects.

CCR6 Expression on B Cells Is Not Required for Clinical or Pathological Presentation of MOG Protein-Induced Experimental Autoimmune Encephalomyelitis despite an Altered Germinal Center Response.

B cells have been implicated in the pathogenesis of multiple sclerosis, but the mechanisms that guide B cell activation in the periphery and subsequent migration to the CNS remain incompletely understood. We previously showed that systemic inflammation induces an accumulation of B cells in the spleen in a CCR6/CCL20-dependent manner. In this study, we evaluated the role of CCR6/CCL20 in the context of myelin oligodendrocyte glycoprotein (MOG) protein-induced (B cell-dependent) experimental autoimmune encephalomyelitis (EAE). We found that CCR6 is upregulated on murine B cells that migrate into the CNS during neuroinflammation. In addition, human B cells that migrate across CNS endothelium in vitro were found to be CCR6+, and we detected CCL20 production by activated CNS-derived human endothelial cells as well as a systemic increase in CCL20 protein during EAE. Although mice that lack CCR6 expression specifically on B cells exhibited an altered germinal center reaction in response to MOG protein immunization, CCR6-deficient B cells did not exhibit any competitive disadvantage in their migration to the CNS during EAE, and the clinical and pathological presentation of EAE induced by MOG protein was unaffected. These data, to our knowledge, provide new information on the role of B cell-intrinsic CCR6 expression in a B cell-dependent model of neuroinflammation.

Risk Factors for Mobility Decline in Community-Dwelling Older Adults: A Systematic Literature Review.

Mobility is essential to maintaining independence for older adults. This systematic review aimed to summarize evidence about self-reported risk factors for self-reported mobility decline; and to provide an overview of published prognostic models for self-reported mobility decline among community-dwelling older adults. Databases were searched from inception to June 2, 2020. Studies were screened by two independent reviewers who extracted data and assessed study quality. Sixty-one studies (45,187 participants) were included, providing information on 107 risk factors. High-quality evidence and moderate/large effect sizes for the association with mobility decline were found for older age beyond 75 years, the presence of widespread pain, and mobility modifications. Moderate-high quality evidence and small effect sizes were found for a further 21 factors. Three model development studies demonstrated acceptable model performance, limited by high risk of bias. These findings should be considered in intervention development, and in developing a prediction instrument for practical application.

Effect of interval compared to continuous exercise training on physiological responses in patients with chronic respiratory diseases: A systematic review and meta-analysis.

BackgroundCurrent evidence suggests that interval exercise training (IET) and continuous exercise training (CET) produce comparable benefits in exercise capacity, cardiorespiratory fitness and symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the effects of these modalities have only been reviewed in patients with COPD. This meta-analysis compares the effectiveness of IET versus CET on exercise capacity, cardiorespiratory fitness and exertional symptoms in patients with chronic respiratory diseases (CRDs). Methods: PubMed, CINHAL, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Nursing and Allied health were searched for randomised controlled trials from inception to September 2020. Eligible studies included the comparison between IET and CET, reporting measures of exercise capacity, cardiorespiratory fitness and symptoms in individuals with CRDs. Results: Thirteen randomised control trials (530 patients with CRDs) with fair to good quality on the PEDro scale were included. Eleven studies involved n = 446 patients with COPD, one involved n = 24 patients with cystic fibrosis (CF) and one n = 60 lung transplantation (LT) candidates. IET resulted in greater improvements in peak work rate (WRpeak) (2.40 W, 95% CI: 0.83 to 3.97 W; p = 0.003) and lower exercise-induced dyspnoea (-0.47, 95% CI: -0.86 to 0.09; p = 0.02) compared to CET; however, these improvements did not exceed the minimal important difference for these outcomes. No significant differences in peak values for oxygen uptake (VO2peak), heart rate (HRpeak), minute ventilation (VEpeak), lactate threshold (LAT) and leg discomfort were found between the interventions. Conclusions: IET is superior to CET in improving exercise capacity and exercise-induced dyspnoea sensations in patients with CRDs; however, the extent of the clinical benefit is not considered clinically meaningful.

Isotype-Switched Autoantibodies Are Necessary To Facilitate Central Nervous System Autoimmune Disease in Aicda-/- and Ung-/- Mice.

B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed Aicda-/- mice is sufficient to fully rescue EAE disease. In addition, we found that the nature of the Ag is an important determinant of EAE severity in Aicda-/- mice because the lack of a diversified BCR does not affect the induction of EAE when immunized with the extracellular domain of rat MOG. To discriminate the effect of either CSR or SHM, we induced EAE in uracil DNA glycosylase-deficient mice (Ung-/-) that exhibit a defect primarily in CSR. We observed that Ung-/- mice exhibit milder clinical disease compared with control mice, concomitant with a reduced amount of anti-MOG IgG1 class-switched Abs that preserved normal affinity. Collectively, these results indicate that CSR plays an important role in governing the incidence and severity of EAE induced with hMOG but not rat MOG.

The risks and benefits of yoga for patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness and safety of yoga interventions on disease symptoms, quality of life and function in patients diagnosed with chronic obstructive pulmonary disease (COPD). DATA SOURCES: Medline/PubMed, Scopus, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched through 6 June 2019. REVIEW METHODS: Randomized controlled trials assessing the effects of yoga on quality of life, dyspnea, exercise capacity, and pulmonary function (FEV1) in patients with COPD were included. Safety was defined as secondary outcome. Mean differences (MD) and standardized mean differences (SMD) with 95% confidence intervals (CIs) were computed. Risk of bias was assessed using the Cochrane tool. RESULTS: Eleven randomized controlled trials with a total of 586 patients were included. Meta-analysis revealed evidence for effects of yoga compared to no treatment on quality of life on the COPD Assessment Test (MD = 3.81; 95% CI = 0.97 to 6.65; P = 0.009, I2 = 70%), exercise capacity assessed by the 6-minute walk test (MD = 25.53 m; 95% CI = 12.16 m to 38.90 m; P = 0.001, I2 = 0%), and pulmonary function assessed by FEV1 predicted (MD = 3.95%; 95% CI = 2.74% to 5.17%; P < 0.001, I2 = 0%). Only the effects on exercise capacity and pulmonary function were robust against methodological bias. Effects were only present in breathing-focused yoga interventions but not in interventions including yoga postures. Adverse events were reported infrequently. CONCLUSION: This meta-analysis found robust effects of yoga on exercise capacity and pulmonary function in patients with COPD. Yoga, specifically yoga breathing techniques, can be an effective adjunct intervention for patients with COPD. Yoga's safety needs to be assessed in more depth in future studies.

Health Behavior Change and Complementary Medicine Use: National Health Interview Survey 2012.

Background and objectives: Complementary and alternative medicine (CAM) use has been associated with preventive health behaviors. However, the role of CAM use in patients' health behaviors remains unclear. This study aimed to determine the extent to which patients report that CAM use motivates them to make changes to their health behaviors. Materials and Methods: This secondary analysis of 2012 National Health Interview Survey data involved 10,201 CAM users living in the United States who identified up to three CAM therapies most important to their health. Analyses assessed the extent to which participants reported that their CAM use motivated positive health behavior changes, specifically: eating healthier, eating more organic foods, cutting back/stopping drinking alcohol, cutting back/quitting smoking cigarettes, and/or exercising more regularly. Results: Overall, 45.4% of CAM users reported being motivated by CAM to make positive health behavior changes, including exercising more regularly (34.9%), eating healthier (31.4%), eating more organic foods (17.2%), reducing/stopping smoking (16.6% of smokers), or reducing/stopping drinking alcohol (8.7% of drinkers). Individual CAM therapies motivated positive health behavior changes in 22% (massage) to 81% (special diets) of users. People were more likely to report being motivated to change health behaviors if they were: aged 18-64 compared to those aged over 65 years; of female gender; not in a relationship; of Hispanic or Black ethnicity, compared to White; reporting at least college education, compared to people with less than high school education; without health insurance. Conclusions: A sizeable proportion of respondents were motivated by their CAM use to undertake health behavior changes. CAM practices and practitioners could help improve patients' health behavior and have potentially significant implications for public health and preventive medicine initiatives; this warrants further research attention.

Yoga for anxiety: A systematic review and meta-analysis of randomized controlled trials.

Yoga has become a popular approach to improve emotional health. The aim of this review was to systematically assess and meta-analyze the effectiveness and safety of yoga for anxiety. Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through October 2016 for randomized controlled trials (RCTs) of yoga for individuals with anxiety disorders or elevated levels of anxiety. The primary outcomes were anxiety and remission rates, and secondary outcomes were depression, quality of life, and safety. Risk of bias was assessed using the Cochrane tool. Eight RCTs with 319 participants (mean age: 30.0-38.5 years) were included. Risk of selection bias was unclear for most RCTs. Meta-analyses revealed evidence for small short-term effects of yoga on anxiety compared to no treatment (standardized mean difference [SMD] = -0.43; 95% confidence interval [CI] = -0.74, -0.11; P = .008), and large effects compared to active comparators (SMD = -0.86; 95% CI = -1.56, -0.15; P = .02). Small effects on depression were found compared to no treatment (SMD = -0.35; 95% CI = -0.66, -0.04; P = .03). Effects were robust against potential methodological bias. No effects were found for patients with anxiety disorders diagnosed by Diagnostic and Statistical Manual criteria, only for patients diagnosed by other methods, and for individuals with elevated levels of anxiety without a formal diagnosis. Only three RCTs reported safety-related data but these indicated that yoga was not associated with increased injuries. In conclusion, yoga might be an effective and safe intervention for individuals with elevated levels of anxiety. There was inconclusive evidence for effects of yoga in anxiety disorders. More high-quality studies are needed and are warranted given these preliminary findings and plausible mechanisms of action.

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology.

Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8(+) T cell responses. In this study, we report that in the context of a CD8(+) T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8(+) T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter-glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-ß receptor (LTßR) in DC are also required for the proliferation of autoreactive CD8(+) T cells, the upregulation of VLA4/LFA1 on activated CD8(+) T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8(+) T cell proliferation, accumulation of CD8(+) T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTßR(-/-) DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTßR/IFN-I axis is essential for programming of CD8(+) T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTßR axis will provide valuable therapeutic insights for treatment of CD8(+) T cell-mediated autoimmune diseases.

A TNF-α-CCL20-CCR6 axis regulates Nod1-induced B cell responses.

Innate immune responses provoke the accumulation of leukocytes at sites of inflammation. In addition to monocytes and granulocytes, B cells also participate in antimicrobial innate immune responses; however, the mechanisms for accumulation of B cells to sites of inflammation are not well understood. To study B cell accumulation following systemic inflammation, we used a model synthetic ligand that stimulates a specific pattern recognition molecule, nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Upon exposure to Nod1 agonists, both B cells and neutrophils rapidly accumulate within the spleen, and dendritic cells migrate into the periarterial lymphoid sheath. Nod1 stimulation led to a marked increase in several chemokines within the spleen, including CXCL13, CCL2, and CCL20. Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway. In contrast, a CCR6/CCL20 chemokine loop instructed rapid increase of B cells in the spleen in response to systemic administration of Nod1 agonists in a TNF-α-dependent manner. Moreover, CCR6 was required to regulate Nod1-mediated B cell responses. These results reveal a novel mechanism of B cells during inflammation and shed light on how B cells participate in innate immune responses to microbial stimulation.

The Safety of Yoga: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

As yoga has gained popularity as a therapeutic intervention, its safety has been questioned in the lay press. Thus, this review aimed to systematically assess and meta-analyze the frequency of adverse events in randomized controlled trials of yoga. MEDLINE/PubMed, Scopus, the Cochrane Library, and IndMED were screened through February 2014. Of 301 identified randomized controlled trials of yoga, 94 (1975-2014; total of 8,430 participants) reported on adverse events. Life-threatening, disabling adverse events or those requiring intensive treatment were defined as serious and all other events as nonserious. No differences in the frequency of intervention-related, nonserious, or serious adverse events and of dropouts due to adverse events were found when comparing yoga with usual care or exercise. Compared with psychological or educational interventions (e.g., health education), more intervention-related adverse events (odds ratio = 4.21, 95% confidence interval: 1.01, 17.67; P = 0.05) and more nonserious adverse events (odds ratio = 7.30, 95% confidence interval: 1.91, 27.92; P < 0.01) occurred in the yoga group; serious adverse events and dropouts due to adverse events were comparable between groups. Findings from this review indicate that yoga appears as safe as usual care and exercise. The adequate reporting of safety data in future randomized trials of yoga is crucial to conclusively judge its safety.

AID-expressing germinal center B cells cluster normally within lymph node follicles in the absence of FDC-M1+ CD35+ follicular dendritic cells but dissipate prematurely.

Upon activation with T-dependent Ag, B cells enter germinal centers (GC) and upregulate activation-induced deaminase (AID). AID(+) GC B cells then undergo class-switch recombination and somatic hypermutation. Follicular dendritic cells (FDC) are stromal cells that underpin GC and require constitutive signaling through the lymphotoxin (LT) ß receptor to be maintained in a fully mature, differentiated state. Although it was shown that FDC can be dispensable for the generation of affinity-matured Ab, in the absence of FDC it is unclear where AID expression occurs. In a mouse model that lacks mature FDC, as well as other LT-sensitive cells, we show that clusters of AID(+)PNA(+)GL7(+) Ag-specific GC B cells form within the B cell follicles of draining lymph nodes, suggesting that FDC are not strictly required for GC formation. However, later in the primary response, FDC-less GC dissipated prematurely, correlating with impaired affinity maturation. We examined whether GC dissipation was due to a lack of FDC or other LTß receptor-dependent accessory cells and found that, in response to nonreplicating protein Ag, FDC proved to be more critical for long-term GC maintenance. Our study provides a spatial-temporal analysis of Ag-specific B cell activation and AID expression in the context of a peripheral lymph node that lacks FDC-M1(+) CD35(+) FDC and other LT-sensitive cell types, and reveals that FDC are not strictly required for the induction of AID within an organized GC-like environment.

BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas.

AIMS: Discriminating small-cell lung carcinoma (SCLC) from large-cell neuroendocrine carcinoma (LCNEC) rests on morphological criteria, and reproducibility has been shown to be poor. We aimed to identify immunohistochemical markers to assist this diagnosis. METHODS AND RESULTS: Gene expression profiling on laser captured frozen tumour samples from eight SCLC and eight LCNEC tumours identified a total of 888 differentially expressed genes (DEGs), 23 of which were validated by qRT-PCR. Antibodies to four selected gene products were then evaluated as immunohistochemical markers on a cohort of 173 formalin-fixed paraffin-embedded (FFPE) SCLC/LCNEC tumour samples, including 26 indeterminate tumours without a consensus diagnosis. Three markers, CDX2, VIL1 and BAI3, gave significantly different results in the two tumour types (P < 0.0001): CDX2 and VIL1 in combination (either marker positive) showed sensitivity and specificity of 81% for LCNEC while BAI3 showed 89% sensitivity and 75% specificity for SCLC. Of the 26 indeterminate tumours 15 (58%) showed an immunophenotype suggesting either SCLC or LCNEC, eight (31%) showed staining of both tumour types, and three (11%) were negative for all markers. CONCLUSION: A panel of three markers, BAI3, CDX2 and VIL1, is a useful adjunct in the diagnosis of these tumour types.

Establishing key components of yoga interventions for musculoskeletal conditions: a Delphi survey.

BACKGROUND: Evidence suggests yoga is a safe and effective intervention for the management of physical and psychosocial symptoms associated with musculoskeletal conditions. However, heterogeneity in the components and reporting of clinical yoga trials impedes both the generalization of study results and the replication of study protocols. The aim of this Delphi survey was to address these issues of heterogeneity, by developing a list of recommendations of key components for the design and reporting of yoga interventions for musculoskeletal conditions. METHODS: Recognised experts involved in the design, conduct, and teaching of yoga for musculoskeletal conditions were identified from a systematic review, and invited to contribute to the Delphi survey. Forty-one of the 58 experts contacted, representing six countries, agreed to participate. A three-round Delphi was conducted via electronic surveys. Round 1 presented an open-ended question, allowing panellists to individually identify components they considered key to the design and reporting of yoga interventions for musculoskeletal conditions. Thematic analysis of Round 1 identified items for quantitative rating in Round 2; items not reaching consensus were forwarded to Round 3 for re-rating. RESULTS: Thirty-six panellists (36/41; 88%) completed the three rounds of the Delphi survey. Panellists provided 348 comments to the Round 1 question. These comments were reduced to 49 items, grouped under five themes, for rating in subsequent rounds. A priori group consensus of ≥80% was reached on 28 items related to five themes concerning defining the yoga intervention, types of yoga practices to include in an intervention, delivery of the yoga protocol, domains of outcome measures, and reporting of yoga interventions for musculoskeletal conditions. Additionally, a priori consensus of ≥50% was reached on five items relating to minimum values for intervention parameters. CONCLUSIONS: Expert consensus has provided a non-prescriptive reference list for the design and reporting of yoga interventions for musculoskeletal conditions. It is anticipated future research incorporating the Delphi guidelines will facilitate high quality international research in this field, increase homogeneity of intervention components and parameters, and enhance the comparison and reproducibility of research into the use of yoga for the management of musculoskeletal conditions.

B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans.

Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby TH17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.

Expression of lymphotoxin-alphabeta on antigen-specific T cells is required for DC function.

During an immune response, activated antigen (Ag)-specific T cells condition dendritic cells (DCs) to enhance DC function and survival within the inflamed draining lymph node (LN). It has been difficult to ascertain the role of the tumor necrosis factor (TNF) superfamily member lymphotoxin-alphabeta (LTalphabeta) in this process because signaling through the LTbeta-receptor (LTbetaR) controls multiple aspects of lymphoid tissue organization. To resolve this, we have used an in vivo system where the expression of TNF family ligands is manipulated only on the Ag-specific T cells that interact with and condition Ag-bearing DCs. We report that LTalphabeta is a critical participant required for optimal DC function, independent of its described role in maintaining lymphoid tissue organization. In the absence of LTalphabeta or CD40L on Ag-specific T cells, DC dysfunction could be rescued in vivo via CD40 or LTbetaR stimulation, respectively, suggesting that these two pathways cooperate for optimal DC conditioning.

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV.

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4 + T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV - participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were 'rescued' after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV - participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral 'blips' in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4 + T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.