By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis ( Mtb ) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb -infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers-cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-Galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb -infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb -infected B6.Sst1S macrophages. As senescent cells are long-lived, non-dividing cells that release tissue-damaging SASP, we treated Mtb -infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells play a causal role in disease progression, and (2) Senolytics merit consideration for human clinical trials against tuberculosis (TB).

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.
Copyright © 2023 Elsevier Inc. All rights reserved.

The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.
Copyright © 2023 Elsevier Inc. All rights reserved.

The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.
Copyright © 2022 Elsevier Inc. All rights reserved.

Loss of oral tolerance (LOT) to gluten, characterized by a T helper 1 (Th1) gluten-specific immune response, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. We hypothesized that certain gut microbes have the capacity to protect against virus-mediated LOT. By using our previously defined reovirus-mediated LOT CeD model, we discovered that the gut colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus-mediated LOT by suppressing the reovirus-induced proinflammatory program of dietary-antigen-presenting CD103 + dendritic cells. Importantly, T. arnold did not affect antiviral host immunity, suggesting that T. arnold -mediated protection against T1L-induced LOT is not attributable to differences in antiviral host responses. Additionally, using gnotobiotic mice, we found that Tritrichomonas arnold colonization is sufficient to protect against reovirus-mediated LOT in the absence of the microbiota. Mechanistically, we show that Tritrichomonas arnold colonization restrains reovirus-induced inflammatory responses in dendritic cells and thus limit their ability to promote Th1 immune responses ex vivo . Finally, our studies using human stool samples support a role for Tritrichomonas sp. colonization in protecting against development of CeD. This study will motivate the design of effective therapies to prevent LOT to gluten in at-risk individuals and to reinstate tolerance to gluten in CeD patients. h4>One Sentence Summary/h4> Tritrichomonas arnold protects against virus-mediated loss of oral tolerance to gluten and is underrepresented in celiac disease patients.