People living with HIV (PLWH) have an increased risk for developing tuberculosis after M. tuberculosis infection, despite anti-retroviral therapy (ART). To delineate the underlying mechanisms, we conducted single cell transcriptomics on bronchoalveolar lavage cells from PLWH on ART and HIV uninfected healthy controls infected with M. tuberculosis ex vivo. We identify an M1-like proinflammatory alveolar macrophage subset that sequentially acquires TNF signaling capacity in controls but not in PLWH. Cell-cell communication analyses reveal interactions between M1-like macrophages and effector memory T cells within TNF superfamily, chemokine, and costimulatory networks in the airways of controls. These interaction networks were lacking in PLWH infected with M. tuberculosis, where anti-inflammatory M2-like alveolar macrophages and T regulatory cells dominated along with dysregulated T cell signatures. Our data support a model in which impaired TNF-TNFR signaling, M2-like alveolar macrophages and aberrant macrophage-T cell crosstalk, lead to ineffective immunity to M. tuberculosis in PLWH on ART.
© 2025. The Author(s).

Abstract People living with HIV (PLWH) have an increased risk for developing tuberculosis (TB) after infection with Mycobacterium tuberculosis (Mtb), despite anti-retroviral therapy (ART). To delineate the underlying mechanisms, we conducted single cell transcriptomics on bronchoalveolar lavage (BAL) cells from PLWH on ART and HIV uninfected healthy controls (HC) infected with Mtb ex vivo. We identified an M1-like proinflammatory alveolar macrophage (AM) subset that sequentially acquired TNF signaling capacity in HC but not in PLWH. Cell-cell communication analyses revealed robust interactions between M1-like AMs and effector memory T cells within TNF superfamily, chemokine, and costimulatory networks in the airways of HC. These interaction networks were lacking in PLWH infected with Mtb, where anti-inflammatory M2-like AMs and T regulatory cells dominated along with dysregulated T cell signatures. Our data support a model in which impaired TNF-TNFR signaling, and aberrant AM-T cell crosstalk, lead to ineffective immunity to Mtb in PLWH on ART.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

ABSTRACT The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report the first patient with SHARPIN deficiency, manifesting fever, arthritis, colitis, chronic otitis media and hepatic glycogenosis but unexpectedly, not associated with dermatologic manifestations. Mechanistically, fibroblasts and B cells from patients with all three LUBAC deficiencies showed attenuated canonical NF-B response and propensity to apoptosis mediated by TNF superfamily members. Furthermore, the SHARPIN deficient patient showed substantial reduction of adenoidal germinal center B cell development. Treatment of the SHARPIN deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for apoptosis-mediated immune dysregulation in humans.

Neonatal immune-microbiota co-development is poorly understood, yet age-appropriate recognition of - and response to - pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 preterm and 119 full-term infants from birth through one year of age, we found that postmenstrual age or weeks from conception is a central factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained; however, by either age metric and are instead shaped by discrete perinatal and postnatal events. Most strikingly, we establish that prenatal antibiotics or infection disrupt the normal T cell population developmental trajectory, influencing subsequent respiratory microbial colonization and predicting respiratory morbidity. In this way, early exposures predict the postnatal immune-microbiota axis trajectory, placing infants at later risk for respiratory morbidity in early childhood.
© 2022 The Author(s).