Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease.

Mucosal-associated invariant T (MAIT) cells have been implicated in various inflammatory diseases of barrier organs, but so far, their role in kidney disease is unclear. Here we report that MAIT cells that recognize their prototypical ligand, the vitamin B2 intermediate 5-OP-RU presented by MR1, reside in human and mouse kidneys. Single cell RNAseq analysis reveals several intrarenal MAIT subsets, and one, carrying the genetic fingerprint of tissue-resident MAIT17 cells, is activated and expanded in a murine model of crescentic glomerulonephritis (cGN). An equivalent subset is also present in kidney biopsies of patients with anti-neutrophil cytoplasmatic antibody (ANCA)-associated cGN. MAIT cell-deficient MR1 mice show aggravated disease, whereas B6-MAITCAST mice, harboring higher MAIT cell numbers, are protected from cGN. The expanded MAIT17 cells express anti-inflammatory mediators known to suppress cGN, such as CTLA-4, PD-1, and TGF-ß. Interactome analysis predicts CXCR6 - CXCL16-mediated cross-talk with renal mononuclear phagocytes, known to drive cGN progression. In line, we find that cGN is aggravated upon CXCL16 blockade. Finally, we present an optimized 5-OP-RU synthesis method which we apply to attenuating cGN in mice. In summary, we propose that CXCR6+ MAIT cells might play a protective role in cGN, implicating them as a potential target for anti-inflammatory therapies.

Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites.

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

Corona was scary, lockdown was worse: A mixed-methods study of community perceptions on COVID-19 from urban informal settlements of Mumbai.

The COVID-19 pandemic has magnified the multiple vulnerabilities of people living in urban informal settlements globally. To bring community voices from such settlements to the center of COVID-19 response strategies, we undertook a study in the urban informal settlements of Dharavi, Mumbai, from September 2020-April 2021. In this study, we have examined the awareness, attitudes, reported practices, and some broader experiences of the community in Dharavi with respect to COVID-19. We have used a mixed-methods approach, that included a cross-sectional survey of 468 people, and in-depth interviews and focus group discussions with 49 people living in this area. Data was collected via a mix of phone and face-to-face interviews. We have presented here the descriptive statistics from the survey and the key themes that emerged from our qualitative data. People reported high levels of knowledge about COVID-19, with television (90%), family and friends (56%), and social media (47%) being the main sources of information. The knowledge people had, however, was not free of misconceptions and fear; people were scared of being forcefully quarantined and dying alone during the early days of COVID-19. These fears had negative repercussions in the form of patient-related stigma and hesitancy in seeking healthcare. A year into the pandemic, however, people reported a shift in attitudes from 'extreme fear to low fear' (67% reported perceiving low/no COVID risk in October 2020), contributing to a general laxity in following COVID-appropriate behaviors. Currently, the community is immensely concerned about the revival of livelihoods, that have been adversely impacted due to the lockdown in 2020 as well as the continued 'othering' of Dharavi for being a COVID hotspot. These findings suggest that urban informal settlements like Dharavi need community-level messaging that counters misinformation and denial of the outbreak; local reinforcement of COVID-appropriate behaviours; and long-term social protection measures.

Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection.

Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.

Conventional NK Cells and Type 1 Innate Lymphoid Cells Do Not Influence Pathogenesis of Experimental Glomerulonephritis.

Innate lymphoid cells (ILCs) that express NK cell receptors (NCRs) and the transcription factor T-bet populate nonlymphoid tissues and are crucial in immune responses against viral infections and malignancies. Recent studies highlighted the heterogeneity of this ILC population and extended their functional spectrum to include important roles in tissue homeostasis and autoimmunity. In this article, we provide detailed profiling of NCR+T-bet+ ILC populations in the murine kidney, identifying conventional NK (cNK) cells and type 1 ILCs (ILC1s) as the two major subsets. Induction of renal inflammation in a mouse model of glomerulonephritis did not substantially influence abundance or phenotype of cNK cells or ILC1s in the kidney. For functional analyses in this model, widely used depletion strategies for total NCR+ ILCs (anti-NK1.1 Ab application) and cNK cells (anti-asialoGM1 serum application) were unreliable tools, because they were accompanied by significant off-target depletion of kidney NKT cells and CD8+ T cells, respectively. However, neither depletion of cNK cells and ILC1s in NKT cell-deficient mice nor specific genetic deletion of cNK cells in Ncr1 Cre/wt × Eomes fl/fl mice altered the clinical course of experimental glomerulonephritis. In summary, we show in this article that cNK cells and ILC1s are dispensable for initiation and progression of immune-mediated glomerular disease and advise caution in the use of standard Ab depletion methods to study NCR+ ILC function in mouse models.

"Everybody breastfeeds if they have milk": factors that shape exclusive breastfeeding practices in informal settlements of Mumbai, India.

Background: In India, though breastfeeding is universally practiced, exclusive breastfeeding (EBF) rates in urban informal settlements are low; and health programs face several challenges in promoting EBF. In this study, ensconced in one program area of a non-government organization, we focused on "positive deviant"- mothers who were able to practice EBF for six months and attempted to delineate factors that shaped their EBF practices. Typically, qualitative research from Lower and Middle Income countries on EBF has focused on understanding why women do not practice EBF; the converse perspective taken in this study has been less explored. Methods: We employed the positive deviance approach which contends that important programmatic learnings can be attained from persons who adopt positive behaviours. We conducted twenty-five diverse, purposively sampled case-studies of "positive deviant" mothers from two urban informal settlements in Mumbai; and analysed these using a framework approach. The results were summarised using a socioecological framework (consisting of individual, interpersonal, organizational and environment levels). Results: We found that mothers typically construed EBF as not giving breastmilk substitutes. Giving the infant minor supplements (water, honey) was not considered a violation of the EBF practice. The main themes that emerged as influencers of EBF included: at individual level, perceptions of having adequate milk; at interpersonal level, having role models who practiced EBF and having family support; at organizational level, advice from health workers (which was purported to play a secondary role); and at environmental level, financial constraints that limited access to supplements. One important finding was that women who practiced EBF could not always do it optimally; we encountered several instances of "poor EBF" practices, where mothers had breastfed infants inconsistently, allowing for long gaps between feeds, and had continued EBF even after six months. Conclusions: There is an urgent need for health programs to clarify the meaning of EBF and counsel against "poor EBF" practices. Messages received by women from immediate family on EBF were powerful and families play an important role in the actualization of optimal EBF practices. Hence, it is imperative to counsel entire families on EBF rather than women alone.

Conflict, crisis, and abuse in Dharavi, Mumbai: experiences from six years at a centre for vulnerable women and children.

Nayreen Daruwalla and colleagues describe the Centre for Vulnerable Women and Children, which serves clients coping with crisis and violence in the urban setting of Dharavi, Mumbai.