Apoptosis in response to microbial infection induces autoreactive TH17 cells

Campisi, Laura; Barbet, Gaëtan; Ding, Yi; Esplugues, Enric; Flavell, Richard A.; Blander, J. Magarian

doi:10.1038/ni.3512

Cited by 83 publications

(72 citation statements)

References 59 publications

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“…S14 and table S1) (26). We tested whether E. gallinarum –immune interactions, possibly mediated by the AhR pathway, induced Th17 and T follicular helper (Tfh) cells in vivo that are crucial for systemic autoantibody production (28, 29). Broad-spectrum antibiotic or vancomycin treatment in (NZW × BXSB)F 1 mice reduced levels of Th17 cells, Tfh cells, and their cytokine signatures (fig.…”

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confidence: 99%

Translocation of a gut pathobiont drives autoimmunity in mice and humans

Vieira

Hiltensperger

Kumar

et al. 2018

Science

596

452

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Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and Tcells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.

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confidence: 99%

Translocation of a gut pathobiont drives autoimmunity in mice and humans

Vieira

Hiltensperger

Kumar

et al. 2018

Science

596

452

View full text Add to dashboard Cite

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“…30,31 Another possibility, based on recent studies in Citrobacter rodentium intestinal infection in mice, could be apoptosis of infected host cells that enables presentation of self-antigens, leading to generation of autoreactive T cells. 32 Thus, there exist several mechanisms by which Mtb and retinal antigen-driven immune responses coexist in TBU eyes, although the sequence of events leading to this unique milieu needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Autoreactive T Cells in Immunopathogenesis of TB-Associated Uveitis

Tagirasa

Parmar

Barik

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Intraocular inflammation in tuberculosis-associated uveitis (TBU) is usually widespread, and responds unpredictably to treatment. Herein, we analyze the intraocular Tcell response in TBU for its surface phenotype, antigenic specificity, and functional characteristics to explain the above observations. METHODS. We isolated T cells from vitreous humor samples of patients with TBU and non-TB uveitis (controls). These were directly stained for surface markers CD4, CD8, CD45RO, CD45RA, CCR7, as well as intracellular cytokines IFN-c, TNF-a, and IL-17 and analyzed on flow cytometry. Antigenic specificity was determined by activating with Mycobacterium tuberculosis-specific antigen Early Secreted Antigenic Target-6 (ESAT-6) or retinal crude extract (RCE). Activation-induced cell death (AICD) characteristics of each T-cell population were analyzed by staining for PI-Annexin V, Fas-FasL, phospho-Akt, and phospho-Erk1/2. RESULTS. Immunophenotyping of vitreous humor samples demonstrated polyfunctional effector and central memory CD4þ T helper cells coexpressing IFN-c, TNF-a, and IL-17. Both ESAT-6 and RCE (autoreactive) specificity was found in T cells extracted from TBU samples; however, the mycobacterial and autoreactive T-cell populations differed in their sensitivity to AICD. Autoreactive T cells appeared to resist AICD through decreased expression of apoptotic markers, FasL and caspase-3, sustained phosphorylation of Akt, and lowered Erk1/2 activity.CONCLUSIONS. Autoreactive T cells are present in TBU eyes and are relatively resistant to AICD. An understanding of this epiphenomenon could be crucial in planning treatment of TBU patients, and interpreting response to anti-TB therapy.

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“…Experimental data rarely challenge established dogma; instead, concepts must evolve and then experiments investigate these hypotheses [11]. Apoptosis of infected cells has recently been shown to induce self-reactive T cells to promote auto-inflammation in other infections [12], and extensive macrophage apoptosis occurs in TB, providing a potential central mechanism. Whilst it may seem implausible that Mtb induces autoimmunity to transmit, such ingenious immunological deception may explain why pathological processes in TB remain so enigmatic.…”

Section: Discussionmentioning

confidence: 99%