Biology subjects

Kamenyeva, O.

Publications and source records attributed to Kamenyeva, O..

8 recordsLinked to original sources

bioRxiv2026

T-bet marks contact-capable regulatory T cells embedded within Th1-dendritic cell networks in skin-draining lymph nodes

Regulatory T cells (Tregs) adapt to inflammatory environments while preserving Foxp3-dependent suppressive identity. In type 1 inflammation, Tregs can upregulate T-bet, but whether T-bet Tregs represent a stable regulatory subset or exhibit plasticity toward an effector-like state remains incompletely understood. To probe the positioning and interactions of T-bet Tregs during type 1 inflammation, we performed live lymph node section microscopy in T-bet-ZsGreen Foxp3-RFP dual-reporter mice during a subcutaneous complete Freunds adjuvant (CFA) challenge. T-bet Tregs accumulated rapidly in the draining lymph nodes within 24 hours, coincident with the appearance of T-bet dendritic cells (DCs) and Th1-like CD4 T cells. Analysis of lymph node sections revealed that T-bet Tregs were incorporated into Th1-DC contact networks, displaying increased contact frequency and contact volume compared with T-bet- Tregs. In parallel, flow cytometric analysis of the immune response showed that T-bet Tregs maintained a stable regulatory profile distinct from T-bet effector T cells, with retained high expression of Foxp3 and regulatory-associated surface molecules including FR4, CD25, Nrp-1, CD39, and GARP. They also expressed elevated adhesion and activation-associated molecules, including LFA-1, ICOS, PD-1, CD44, and CD103 compared with T-bet- Tregs, and were enriched for CD103 cells across the inflammatory time course. Adoptive transfer studies further showed that pre-existing T-bet expression enhanced recovery of antigen-specific Tregs from CFA-draining lymph nodes in a context-dependent manner, whereas T-bet expression did not confer a unique advantage in canonical in vitro suppression of Th1 proliferation. Together, these findings identify T-bet Tregs as a contact-capable regulatory subset embedded within early Th1-DC networks during the priming phase of type 1 inflammation rather than a destabilized or effector-converted Treg population.

immunology↗

bioRxiv2025

Alternatively activated monocyte-derived myeloid cells promote extracellular pathogen persistence within pulmonary fungal granulomas.

Inhaled fungal pathogens often generate granuloma-contained latent infections that can reactivate to cause invasive disease. However, the mechanisms underlying the inability to generate sterilizing immunity against latent infection remains poorly understood. Here, we leveraged spatial transcriptomics and flow cytometry to characterize the immune dynamics and cellular architecture of cryptococcal granulomas. Using fate mapping and murine genetic tools, we demonstrate that alternative activation of monocyte-derived myeloid cells by CD4+ T helper 2 cells antagonizes pulmonary fungal clearance during latent infection. In contrast to the prevailing view in the field, we find that alternatively activated myeloid cells are not an intrinsic replication niche for the fungus and more broadly, Cryptococcus predominantly resides in the extracellular environment. We propose a T helper 2 cell-myeloid circuit establishes a local immunosuppressive environment to drive extracellular fungal persistence, which could be leveraged as a new target for host-directed therapy to treat latent fungal infections.

immunology↗

bioRxiv2024

Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis

In murine models of visceral leishmaniasis (VL), parasitization of resident Kupffer cells (resKCs) is responsible for early growth of Leishmania infantum in the liver, which leads to granuloma formation and eventual parasite control. We employed the chronic VL model, and revealed an open niche established by KCs death and their migration outside of the sinusoids, resulting in their gradual replacement by monocyte-derived KCs (moKCs). While early granulomas were composed of resKCs, late granulomas were found outside of the sinusoids and contained resKC-derived macrophages, and monocyte-derived macrophages (momacs). ResKCs and moKCs within the sinusoids were identified as homeostatic/regulatory cells, while resKC-derived macrophages and momacs within late granulomas were pro-inflammatory. Despite the infection being largely confined to the resKC-derived macrophages, in the absence of monocyte recruitment, parasite control was strongly compromised. Macrophage heterogeneity, involving migration and reprogramming of resKCs, along with recruitment of monocyte-derived cells, is a hallmark of granuloma maturation and hepatic immunity in VL.

immunology↗

bioRxiv2023

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology. Significance statementMultisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.

immunology↗

bioRxiv2022

Rapid GPR183-mediated recruitment of eosinophils to the lung after Mycobacterium tuberculosis infection

Influx of eosinophils into the lungs is typically associated with type-II responses during allergy, fungal and parasitic infections. However, we previously reported that eosinophils accumulate in lung lesions during type-I inflammatory responses to Mycobacterium tuberculosis (Mtb) in humans, macaques, and mice where they contribute to host resistance. Here we show eosinophils migrate into the lungs of macaques and mice as early as one week after Mtb-exposure. In mice this influx was CCR3 independent and instead required cell-intrinsic expression of the oxysterol-receptor GPR183, which is highly expressed on human and macaque eosinophils. Murine eosinophils interacted directly with bacilli-laden alveolar macrophages, which upregulated the oxysterol-synthesizing enzyme Ch25h, and eosinophil recruitment was impaired in Ch25h deficient mice. Our findings show that eosinophils are among the first cells from circulation to sense and respond to Mtb infection of alveolar macrophages and reveal a novel role for GPR183 in the migration of eosinophils into lung tissue. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/480919v1_ufig1.gif" ALT="Figure 1"> View larger version (105K): org.highwire.dtl.DTLVardef@e8cd29org.highwire.dtl.DTLVardef@1f5769borg.highwire.dtl.DTLVardef@3dce9borg.highwire.dtl.DTLVardef@1c75587_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSIn mice and macaques eosinophils accumulate early in Mtb-infected lungs preceding neutrophils Eosinophils interact with Mtb-infected cells in the alveoli in mice Early pulmonary eosinophil migration occurs independently of CCR3 in mice Early lung migration in mice requires Ch25h and eosinophil-intrinsic GPR183 expression

immunology↗

bioRxiv2020

Unrestrained Gαi2 Signaling Disrupts Normal Neutrophil Trafficking, Aging, and Clearance

Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptor triggered heterotrimeric G-protein Gi{beta}{gamma} signaling, whose magnitude and kinetics are governed by RGS protein/Gi interactions. Yet how in totality RGS proteins shape neutrophil chemoattractant receptor activated responses remains unclear. Here, we show that C57Bl/6 neutrophils with genomic knock-in of a mutation that disables all RGS protein-Gi2 interactions (G184S) cannot properly balance chemoattractant receptor signaling, nor appropriately respond to inflammatory insults. Mutant neutrophils accumulate in bone marrow, spleen, lung, and liver; despite neutropenia and an intrinsic inability to properly mobilize from bone marrow. In vitro they rapidly adhere to ICAM-1 coated plates, but poorly adhere to blood vessel endotheliums in vivo. Those few neutrophils that cross endotheliums migrate haphazardly. Following Concanavalin-A administration fragmented G184S neutrophils accumulate in liver sinusoids leading to thrombo-inflammation and perivasculitis. Thus, neutrophil Gi2/RGS protein interactions limit and facilitate Gi2 signaling allowing normal neutrophil trafficking, aging, and clearance.

immunology↗

bioRxiv2020

PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with PD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in PD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of PD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

immunology↗

bioRxiv2020

The role of dermis resident macrophages and their interaction with neutrophils in the early establishment of Leishmania major infection transmitted by sand fly bite

There is substantial experimental evidence to indicate that Leishmania infections that are transmitted naturally by the bites of infected sand flies differ in fundamental ways from the inflammatory and immune reactions initiated by needle inocula. We have used flow cytometry and intravital microscopy (IVM) to reveal the heterogeneity of sand fly transmission sites with respect to the subsets of phagocytes in the skin that harbor L. major within the first hours and days after infection. By flow cytometry analysis, dermis resident macrophages (TRMs) were on average the predominant infected cell type at 1 hr and 24 hr. By confocal IVM, the co-localization of L. major and neutrophils varied depending on the proximity of deposited parasites to the presumed site of vascular damage, defined by the highly localized swarming of neutrophils. Some of the dermal TRMs could be visualized acquiring their infections via transfer from or efferocytosis of parasitized neutrophils, providing direct evidence for the "Trojan Horse" model. The role of neutrophil engulfment by dermal TRMs and the involvement of the Tyro3/Axl/Mertk family of receptor tyrosine kinases in these interactions and in sustaining the anti-inflammatory program of dermal TRMs was supported by the effects observed in neutrophil depleted and in Axl-/-Mertk-/- mice. The Axl-/-Mertk-/- mice also displayed reduced parasite burdens but more severe pathology following L. major infection transmitted by sand fly bite. SummarySand flies transmit Leishmania major which causes cutaneous leishmaniasis in humans and in non-human hosts. Our analyses of sand fly transmission sites of L. major in the mouse skin revealed that dermis resident macrophages (TRM) were the predominant phagocytes to take up the parasite within the first 24 hr post-bite. The early involvement of neutrophils varied depending on the proximity of deposited parasites to the site of tissue damage around which the neutrophils coalesced. By intra-vital microscopy, some of the dermal TRMs could be visualized acquiring their infections by direct transfer from or phagocytosis of parasitized neutrophils. The involvement of the Tyro3/Axl/Mertk family of receptor tyrosine kinases in these cellular interactions and in sustaining the anti-inflammatory functions of dermal TRMs was supported by the reduced parasite burdens but more severe pathology observed in Axl-/-Mertk-/- mice. The heterogeneity of sand fly transmission sites with respect to the dose of parasites and the early cellular interactions described here likely contribute to the wide range of infection outcomes that are associated with natural transmission of L. major observed in mouse models and possibly humans.

immunology↗