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    B Cells Producing Type I IFN Modulate Macrophage Polarization in Tuberculosis. Bénard Alan,Sakwa Imme,Schierloh Pablo,Colom André,Mercier Ingrid,Tailleux Ludovic,Jouneau Luc,Boudinot Pierre,Al-Saati Talal,Lang Roland,Rehwinkel Jan,Loxton Andre G,Kaufmann Stefan H E,Anton-Leberre Véronique,O'Garra Anne,Sasiain Maria Del Carmen,Gicquel Brigitte,Fillatreau Simon,Neyrolles Olivier,Hudrisier Denis American journal of respiratory and critical care medicine RATIONALE:In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or noninfectious diseases via antibody-independent mechanisms. In tuberculosis (TB), B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES:To document the role of B cells in TB in an unbiased manner. METHODS:We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of patients with TB. MEASUREMENTS AND MAIN RESULTS:B cells isolated from Mtb-infected mice displayed a STAT1 (signal transducer and activator of transcription 1)-centered signature, suggesting a role for IFNs in B-cell response to infection. B cells stimulated in vitro with Mtb produced type I IFN, via a mechanism involving the innate sensor STING (stimulator of interferon genes), and antagonized by MyD88 (myeloid differentiation primary response 88) signaling. In vivo, B cells expressed type I IFN in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with TB. Type I IFN expression by B cells induced an altered polarization of macrophages toward a regulatory/antiinflammatory profile in vitro. In vivo, increased provision of type I IFN by B cells in a murine model of B cell-restricted Myd88 deficiency correlated with an enhanced accumulation of regulatory/antiinflammatory macrophages in Mtb-infected lungs. CONCLUSIONS:Type I IFN produced by Mtb-stimulated B cells favors macrophage polarization toward a regulatory/antiinflammatory phenotype during Mtb infection. 10.1164/rccm.201707-1475OC
    Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression. Sallin Michelle A,Kauffman Keith D,Riou Catherine,Du Bruyn Elsa,Foreman Taylor W,Sakai Shunsuke,Hoft Stella G,Myers Timothy G,Gardina Paul J,Sher Alan,Moore Rashida,Wilder-Kofie Temeri,Moore Ian N,Sette Alessandro,Lindestam Arlehamn Cecilia S,Wilkinson Robert J,Barber Daniel L Nature microbiology Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (T1) cells in the lung tissue parenchyma, but its induction does not require T1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8 or Ifng CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8 and Ifng CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule. 10.1038/s41564-018-0231-6
    Immunometabolism during Mycobacterium tuberculosis Infection. Howard Nicole C,Khader Shabaana A Trends in microbiology Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism. 10.1016/j.tim.2020.04.010