Biology subjects

Mattapallil, M. J.

Publications and source records attributed to Mattapallil, M. J..

6 recordsLinked to original sources

bioRxiv2025

Gut microbial interaction networks control autoimmunity to neuroretina

The gut microbiome influences the development of immune-mediated inflammatory diseases, including autoimmune uveitis, a sight-threatening ocular inflammation driven by retina-specific T cells1. Using a model of spontaneous autoimmune uveitis (sEAU) we showed that gut commensals provide immune stimuli that trigger disease2. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensals from healthy human donors was sufficient to provoke disease. Severity of sEAU correlated with expansion of Akkermansia and contraction of short-chain fatty acid (SCFA)-producing Firmicutes, followed by decreased SCFA levels and a dominant gut Th1 effector response. Mechanistic gain-of-function experiments, enriching GF sEAU mice with Akkermansia, reproduced these microbiome, metabolite and immune phenotype shifts, and exacerbated disease, suggesting that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. An inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in patients with uveitis, multiple sclerosis and Crohns disease. These findings reveal a stereotypic gut microbial interaction network that regulates systemic immune balance, and may represent an ecologically conserved mechanism through which the gut microbiome modulates autoimmune and inflammatory diseases.

immunology↗

bioRxiv2025

Laquinimod treatment attenuates EAU by inhibiting both the inductive and effector phases in an APC-dependent manner

PurposeTo evaluate the immunomodulatory effects on experimental autoimmune uveitis (EAU) of the aryl hydrocarbon receptor (AhR) agonist Laquinimod (LAQ), and its active metabolite DELAQ, with a focus on dendritic cell- and T cell-mediated mechanisms. MethodsEAU was induced in mice by active immunization or by adoptive transfer of activated T cells. Mice were treated with LAQ either from the time of immunization or from 7 days after. Effects of LAQ were examined in wild-type, global AhR-knockout, or dendritic cell-conditional AhR knockout mice. Direct vs. indirect effects of AhR agonism on dendritic cells and T cells were studied in vitro using DELAQ, a major active metabolite of LAQ. ResultsLAQ treatment from Day 0 fully suppressed EAU, while delayed treatment (Day 7) provided only partial protection. In the adoptive transfer model, LAQ-treated recipients showed reduced pathology. Global AhR-deficient mice developed severe EAU comparable to that of wild-type mice, with an elevated Th17 response. LAQ-treated mice displayed increased frequencies of cDC1 and FoxP3 regulatory T cells. In vitro, DELAQ activated AhR signaling and induced Ido1 and Ido2 expression in dendritic cells. DELAQ inhibited the activation of naive and memory mouse T cells in an APC-dependent manner, as the response to anti-CD3/CD28 stimulation was unaffected. Importantly, DELAQ suppressed recall responses of human PBMC to tetanus toxoid. ConclusionsLAQ protects against EAU by acting on AhR-expressing antigen-presenting cells to impair both priming and reactivation of pathogenic T cells. Its active metabolite DELAQ does not suppress T cells directly, but re-programs dendritic cells toward a tolerogenic, IDO-expressing phenotype that promotes immune regulation.

immunology↗

bioRxiv2025

Vitamin A is necessary for acquisition, but not for expression or progression, of CNS autoimmunity

Vitamin A (VitA) and its derivative retinoic acid (RA) are essential for immunological responses. In VitA deficient (VAD) mice, acquisition of effector responses is impeded, but little is known about maintenance and expression of previously acquired effector function under the VAD conditions. We examined the impact of VAD on progression of autoimmune diseases using two models of uveitis, experimental autoimmune uveitis (EAU) induced by active immunization and spontaneous uveitis in retina-specific T cell receptor transgenic (R161H) mice, and in the model of experimental autoimmune encephalomyelitis (EAE). VAD was induced by dietary lack of VitA from before birth, or by daily injections of a pan-RA receptor inhibitor BMS493 in adult mice fed with the standard diet. VAD mice were essentially resistant to induction of EAU or EAE and displayed impaired effector T cell responses. Defective priming/acquisition of effector function by VAD T cells was also evident. By contrast, spontaneously uveitic R161H mice fed with VAD diet, in which priming of pathogenic T cells occurs before onset of full VAD, only moderately attenuated uveitis compared to VitA sufficient R161H mice. To reconcile somewhat different results between induced model and spontaneous model of uveitis, we examined EAU in partial VAD mice or adoptive transfer into VAD hosts. The results supported that effector T cells primed in VitA-sufficient environment were able to function in VAD environment and induced EAU. We conclude that although priming of naive T cells in the VAD environment is defective, effector function acquired under VitA sufficient conditions is maintained and can be expressed under VAD conditions. Because dietary lack of VitA is rarely profound and may be seasonal, our findings may shed light on immunity and autoimmunity in geographical regions where dietary VitA is limiting.

immunology↗

bioRxiv2025

Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity

Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identify trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis (C. mast) as a potent stimulator of IL-17 production by {gamma}{delta} T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and {gamma}{delta} TCR signaling, which also supports endogenous {gamma}{delta} T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing {gamma}{delta} T cell immunity and protect against pathogenic corneal infection. Our findings establish TMCM as a key mediator of commensal-driven immune defense, highlighting its potential as a {gamma}{delta} T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@63139forg.highwire.dtl.DTLVardef@9d6978org.highwire.dtl.DTLVardef@775e37org.highwire.dtl.DTLVardef@ca84b6_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LICorynomycolates enable ocular C. mast colonization and protective IL-17 immunity C_LIO_LITMCM drives IL-17 from {gamma}{delta} T cells through TCR and IL-1R signaling C_LIO_LI{gamma}{delta} TCR signaling maintains the expression of endogenous IL-1R1 C_LIO_LISynthetic TMCM mimics the ability of C. mast to induce {gamma}{delta} T cell immunity in the eye C_LIO_LITMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential C_LI

immunology↗

bioRxiv2025

Ocular immune privilege in action: the living eye imposes unique regulatory and anergic gene signatures on uveitogenic T cells

Despite ocular immune privilege, circulating retina-specific T cells can trigger autoimmune uveitis, yet intraocular bleeding--a relatively common event--rarely leads to disease. Using an in vivo immune privilege model, we previously reported that all naive retina-specific T cells entering the eye become primed in situ; about Ob% become FoxpO+ T-regulatory cells (Tregs), while the rest fail to induce pathology. Here, single-cell transcriptomics and functional validation revealed distinct phenotypes in both populations: ocular Tregs were highly suppressive, whereas non-Tregs expressed suppression- and anergy-associated genes and lacked regulatory function. Trajectory analyses suggested that Tregs and anergic cells arise from a common proliferative precursor in parallel, rather than sequentially. Our data indicate a key checkpoint governing the divergence of anergic and regulatory fates. These findings provide molecular-level insights into ocular immune privilege and may inform strategies to silence autoimmune effector cells or reverse T cell unresponsiveness in cancer, vaccination, or chronic infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/640701v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1e13f5org.highwire.dtl.DTLVardef@b065feorg.highwire.dtl.DTLVardef@f83014org.highwire.dtl.DTLVardef@1ca8f0_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIEye-primed retina-specific T cells develop distinct tolerance-associated phenotypes. C_LIO_LIEye-induced anergic T cells remain hyporesponsive to antigen re-stimulation. C_LIO_LIRegulatory and anergic T cells differentiate in parallel from a common precursor. C_LIO_LIInduction of T cell anergy is a novel feature of ocular immune privilege. C_LI

immunology↗

bioRxiv2024

TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival {gamma}{delta} T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival V{gamma}4 T cells through a combination of {gamma}{delta} TCR ligation and IL-1 signaling. Here, we identify V{gamma}6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that V{gamma}6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, I{kappa}B{zeta}, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal {gamma}{delta} T cells. SummaryOcular commensal Corynebacterium mastitidis (C. mast) induces IL-17 responses from {gamma}{delta} T cells by activating TLR2 signaling. {gamma}{delta} T cell-intrinsic TLR2 stimulation can increase Il17a transcription and promote fatty acid oxidation, favoring {gamma}{delta} T cell IL-17A responses. Highlights(1) V{gamma}6 T cells are a major C. mast-responsive subset in the conjunctiva (2) TLR2-deficient mice exhibit reduced {gamma}{delta} T cell responses to ocular commensal bacteria. (3) {gamma}{delta} T cell-intrinsic TLR2 deficiency causes defects of fatty acid oxidation and IL-17A production in a {gamma}{delta} subset-specific manner. (4) The transcription factor, I{kappa}B{zeta} is upregulated by TLR2 stimulation and supports {gamma}{delta} IL-17A production through fatty acid oxidation. O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/587519v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1d1ba87org.highwire.dtl.DTLVardef@2d17d9org.highwire.dtl.DTLVardef@78e846org.highwire.dtl.DTLVardef@1d96dc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗