Biology subjects

Linder, A. H.

Publications and source records attributed to Linder, A. H..

3 recordsLinked to original sources

bioRxiv2024

PPARγ downregulation in colonic CD8+ T cells results in epithelial barrier disruption in people with HIV on antiretroviral therapy

A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a novel mechanism by which immunometabolic defects in colon resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cell leads to loss of intestinal epithelial homeostasis. These results identify potential new strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.

immunology↗

bioRxiv2023

Colon resident CD8+ T cells from people with HIV on antiretroviral therapy exhibit mitochondrial dysfunction and impaired responses

CD8+ tissue-resident memory T cells (CD8+ TRM) play an important role in mediating immune responses against HIV in the gastrointestinal (GI) mucosa. Antiretroviral therapy (ART) successfully supresses HIV replication in the blood, but fails to restore GI homeostasis, particularly within gut associated lymphoid tissue (GALT). The importance of cellular metabolism in shaping CD8+ TRM antiviral function has emerged as a crucial aspect of general immunoregulation. To gain better insight into the immunoregulation of CD8+ TRM during HIV, we characterized the function of blood and colon CD8+ T cells in people with HIV (PWH) on ART and HIV-uninfected individuals. We show that a higher proportion of activated CD8+ TRM persisted in the colon of PWH on ART, and these cells exhibited weaker immune response and compromised mitochondrial function compared to their peripheral counterparts. We also observed decreased mitochondrial function in CD8+ T cell in the colon compared to peripheral blood in PWH on ART. The study indicates that mitochondrial bioenergetic properties may be an indicator of colonic CD8+ TRM dysfunction in PWH on ART and highlights the importance of understanding cellular metabolism in shaping CD8+ TRM function to develop targeted immunotherapies for PWH.

immunology↗

bioRxiv2022

Tobacco smoke exposure results in recruitment of inflammatory airspace monocytes and accelerated growth of Mycobacterium tuberculosis

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current- and never-smokers by performing single-cell RNA-sequencing (scRNA-seq), flow cytometry, and functional assays. We observed enrichment of immature inflammatory monocytes in the lungs of smokers compared to non-smokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease (COPD). Using integrative scRNA-seq and flow cytometry, we identify CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provide evidence that recruitment of monocytes into the lung is mediated by CCL11 binding to CCR2. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared to mature macrophages. This elevated Mtb growth could be inhibited with an anti-inflammatory small molecule, providing a direct connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to recruitment of immature inflammatory monocytes from the periphery to the lung via CCL11-CCR2 interactions, which results in the accumulation of these Mtb permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies novel host-directed therapies to reduce the burden of TB among those who smoke. One Sentence SummaryInflammatory monocytes are recruited to the airways of smokers where they may contribute to more rapid growth of Mycobacterium tuberculosis in the lungs.

immunology↗