Biology subjects

Dikiy, S.

Publications and source records attributed to Dikiy, S..

8 recordsLinked to original sources

bioRxiv2026

NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity

The gut microbiota influences cancer immunotherapy, but how interactions among host microbial sensors determine the activity of individual bacteria remains unclear. Here, we show that NOD2 restrains TLR2-dependent antitumor immunity induced by Lactiplantibacillus plantarum. Oral administration of live or heat-killed L. plantarum enhanced immune checkpoint blockade efficacy in mouse tumor models. This activity required host TLR2 signaling and was diminished by disruption of bacterial lipoprotein. In contrast, NOD2 deficiency enhanced tumor control, intratumoral interferon-associated programs, and T cell activation. NOD2 deficiency also amplified chemokine and interferon-associated responses to L. plantarum and the synthetic TLR2 agonist Pam3CSK4 in myeloid cells. Genetic loss or pharmacological inhibition of NOD2 improved Pam3CSK4-mediated tumor control in combination with checkpoint blockade. These findings identify NOD2 as a functional checkpoint on TLR2-driven antitumor immunity and demonstrate that interactions between host microbial-sensing pathways shape the therapeutic activity of commensal bacteria and innate immune agonists.

immunology↗

bioRxiv2026

Metabolically Activated Proteostasis Regulators Reduce Differentiation of CD4+ TH17 Cells

The differentiation of naive CD4+ T cells into effector T cell subsets such as TH1, TH2, TH17 and TREG cells is governed by tightly coordinated activation programmes dependent on T cell receptor (TCR) engagement, co-stimulation, and cytokine signalling. This differentiation process involves regulation of stress-responsive signalling pathways such as the unfolded protein response (UPR) and the oxidative stress response (OSR) to adapt to the physiologic demands specific to distinct T cell subset functions. This suggests that pharmacologically targeting stress-responsive pathways offers a unique opportunity to selectively remodel the differentiation of these different T cell subsets. We previously identified compound AA147 as a metabolically activated proteostasis regulator that can induce both the ATF6 signalling arm of the UPR and, in certain cell types, the NRF2-regulated arm of the OSR. (Paxman et al., 2018; Plate et al., 2016) Here, we show that treatment with AA147 selectively reduces differentiation of pro-inflammatory TH17 cells by promoting degradation of the lineage-specifying transcription factor RORgammat, without impacting the transcription factors of other CD4+ T cell subsets. AA147-dependent reduction in TH17 differentiation is independent of ATF6 activation and involves activation of NRF2, which reduces intracellular reactive oxygen species (ROS) to hinder TH17 cell differentiation. Apart from RORgammat, we found that AA147 decreases expression of the TCR-responsive factor IRF4, thus suppressing production of select effector cytokines across effector T cells, demonstrating additional ways in which this compound reshapes the activities of these essential T cell subsets. Our results demonstrate the potential for metabolically activated proteostasis regulators such as AA147 to selectively reshape TH17 cell identity while broadly dampening effector cytokine responses across effector T cell subsets, through both NRF2-dependent and independent mechanisms during T cell differentiation.

cell biology↗

bioRxiv2026

Maternal antiviral history synergizes with pregnancy and lactation to transfer intergenerational systemic immunity through IgG in milk

Maternal immune transfer is essential for early-life health, yet whether immune experiences before pregnancy shape maternal physiology to optimize immunity in subsequent offspring is unclear. Here, we show that respiratory viral infection before pregnancy confers robust protection against lethal neonatal influenza through antibodies transferred postpartum in milk. Despite the predominance of IgA in milk, antiviral IgG is indispensable for protection. Pregnancy amplifies pre-existing antiviral B cell responses, while prior infection durably reprograms the mammary gland to promote transfer of circulating antiviral IgG into milk. These antibodies retain their epitope specificity, are enriched for broadly protective influenza epitopes, remain functional after passage through the neonatal intestine, and enter offspring circulation through FcRn to provide protection beyond weaning. Natural transmission of virus from infected offspring to mothers establishes maternal immunity that protects future offspring, revealing a coordinated adaptive program that links maternal immune history, pregnancy, and lactation to optimize intergenerational immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/744935v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1f82cbeorg.highwire.dtl.DTLVardef@41ac81org.highwire.dtl.DTLVardef@1a4538aorg.highwire.dtl.DTLVardef@168bc21_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG HIGHLIGHTSO_LIPreconceptual maternal intranasal influenza infection confers complete neonatal B cell mediated protection against lethal neonatal influenza infection that persists beyond weaning into early adulthood. C_LIO_LIProtection can be transmitted postnatally through milk and is fully dependent on maternal IgG. C_LIO_LIPregnancy enhances rather than suppresses antiviral B cell programs in the mother. C_LIO_LIMilk IgG targets a restricted set of conserved influenza Hemagglutinin epitopes, suggesting selective transfer of broadly protective antibody populations. C_LIO_LIProtective IgG in milk derives from maternal circulation, not from local B cell mammary gland production. C_LIO_LIRespiratory infection before pregnancy induces long-lived vascular, stromal, and epithelial transcriptional remodeling of the mammary gland. C_LIO_LINeonatal Fc Receptor (FcRn) mediated transport of milk IgG into circulation is required for protection. C_LIO_LIInfected neonates transmit virus back to mothers, extending protection to subsequent litters for multi-generation protection. C_LI

immunology↗

bioRxiv2026

T-bet Expressing B cells are Key Determinants of Protective Immunity Against Norovirus Infection

The gastrointestinal tract (GI) is the largest environmental mucosal interface and is exposed to diverse commensal and pathogenic microbes. B cells are a prevalent immune component of the GI tract and its associated secondary lymphoid organs, yet we know little about the diversity and stability of distinct transcriptional programs that modulate B cell responses against different classes of pathogens or environmental perturbations. A subset of B cells defined by expression of the transcription factor T-bet, has been canonically associated with antiviral immunity through IgG production. However, the role of T-bet expressing B cells in mucosal tissues, where IgA responses predominate, is poorly understood. Here, we identify a population of intestinal T-bet+ B cells that, in the absence of overt perturbation, constitutes a minor fraction of intestinal associated B cells and undergoes continuous turnover. In contrast, during enteric viral infection with murine norovirus (MNV), T-bet B cells undergo a marked expansion, with T-bet expression stably maintained in the majority of virus-specific B cells, including IgG2c and IgA switched B cells. Moreover, virus-reactive IgG2c and IgA B cells arise independently rather than through sequential switching, and B cell intrinsic T-bet expression is required for effective germinal center responses but dispensable for IgA class switching. Moreover, T-bet expressing B cells are required for the generation of all MNV-specific circulating IgG and mucosal IgA, and for protection upon re-encounter with the virus. Together, these findings establish T-bet expressing B cells as a specialized B cell subset essential for mucosal immunity and protection against norovirus infection.

immunology↗

bioRxiv2025

Microbiota-derived secondary bile acids promote STING activation and antitumor activity

Microbiota metabolism generates diverse bile acids that are associated with health and disease, but the molecular targets and mechanisms of action for these metabolites have not been fully elucidated. Using deoxycholic acid (DCA) photoaffinity probes, with cholic acid (CA) probe as a comparator, we found many protein targets of microbiota-derived DCA in mammalian cells. Of note, we discovered that DCA binds the transmembrane domain of stimulator of interferon genes (STING), and enhances agonist-induced accumulation of higher-order STING species, type I interferon signaling and antitumor immunity. Moreover, DCA-producing microbiota species enhanced STING agonist-induced antitumor immunity primarily through the activation of natural killer (NK) cells. This reverse chemical microbiology approach revealed an unpredicted mechanism of action for DCA on STING activation and suggests that specific secondary bile acids and their associated microbiota species may promote NK activation and impact the efficacy of STING-targeted therapeutics.

immunology↗

bioRxiv2024

Regulatory T cells restrain skin inflammation by modulating peripheral neuron activation

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we questioned whether regulatory T cells (Treg cells), a T cell subset that suppresses systemic and local inflammation, can modulate activation of peripheral neurons. Short-term ablation of Treg cells increased neuronal activation to noxious stimuli independently from immunosuppressive function. We find that a population of skin Treg cells is highly enriched for Penk expression, a precursor for endogenous opioid enkephalins. Acute depletion of Penk-expressing Treg cells, or cell-specific ablation of Penk in Treg cells increases neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of Treg cells exhibits neuromodulatory activity to restrain inflammation.

immunology↗

bioRxiv2022

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

Regulatory T (Treg) cells represent a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Recent studies of the adaptations of Treg cells to non-lymphoid tissues which enable their specialized immunosuppressive and tissue supportive functions raise questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Using novel genetic tools, we characterized the transcriptional programs of distinct colonic effector Treg cell types. We found that attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR independent functionality appears to facilitate the terminal differentiation of a population of colonic effector Treg cells distinguished by stable expression of immunomodulatory cytokine interleukin-10 (IL-10). Functional studies revealed that this subset of effector Treg cells, but not their expression of IL-10, was indispensable for colonic health. These findings suggest core features of terminal differentiation of effector Treg cells in non-lymphoid tissues and their function therein.

immunology↗

bioRxiv2021

Skin stem cells orchestrate de novo generation of extrathymic regulatory T cells to establish a temporary protective niche during wound healing

Adult stem cells reside in various tissues to govern homeostasis and repair damage. During wound healing, these stem cells must be mobilized to enter the center of the injury where they are exposed to many inflammatory immune cells infiltrating the wounded tissue. While these immune cells are indispensable for preventing infections and clearing dead cells, they can also create a harsh inflammatory environment which could potentially damage the stem cells and prevent their self-renewal and differentiation. Here, using a model of cutaneous wound healing in which hair follicle stem cells (HFSCs) repair the wound, we show that, upon migrating into the wound, skin stem cells acquire a strong immune modulatory capacity which allows them to sculpt a temporary immune suppressive niche for self-protection. We reveal that the HFSCs in the wound bed orchestrate extrathymic differentiation of regulatory T (Treg) cells by providing co-stimulation to the woundinfiltrating CD4 effector T cells. In this way, Treg cells can be generated de novo in close proximity to and can intimately protect HFSCs from the collateral damage inflicted by inflammatory neutrophils. This study uncovered a striking inflammatory adaptation capacity unique to adult tissue stem cells which allows them to shape their own immune suppressive niche during wound repair.

immunology↗