Biology subjects

Churchill, M. J.

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

3 recordsLinked to original sources

bioRxiv2023

Lymphatic vessel transit seeds precursors to cytotoxic resident memory T cells in skin draining lymph nodes

Resident memory T cells (TRM) provide rapid, localized protection in peripheral tissues to pathogens and cancer. While TRM are also found in lymph nodes (LN), how they develop during primary infection and their functional significance remains largely unknown. Here, we track the anatomical distribution of anti-viral CD8+ T cells as they simultaneously seed skin and LN TRM using a model of skin infection with restricted antigen distribution. We find exquisite localization of LN TRM to the draining LN of infected skin. LN TRM formation depends on lymphatic transport and specifically egress of effector CD8+ T cells that appear poised for residence as early as 12 days post infection. Effector CD8+ T cell transit through skin is necessary and sufficient to populate LN TRM in draining LNs, a process reinforced by antigen encounter in skin. Importantly, we demonstrate that LN TRM are sufficient to provide protection against pathogenic rechallenge. These data support a model whereby a subset of tissue infiltrating CD8+ T cells egress during viral clearance, and establish regional protection in the draining lymphatic basin as a mechanism to prevent pathogen spread. One Sentence SummaryT cell egress out of virally infected skin via afferent lymphatic vessels seeds CD8+ resident memory T cells in the draining lymph node.

immunology↗

bioRxiv2023

NAIP-NLRC4 Inflammasome Activation in Tuft Cells Activates a PGD2-ILC3 Signaling Circuit that Protects Against Enteric Infection.

Intestinal epithelial cells (IEC) use innate sensing pathways to distinguish pathogens from commensals. One such pathway, the NAIP--NLRC4 inflammasome, initiates extrusion of infected IEC and mediator release upon cytosolic bacterial sensing. Tuft cells are primarily known for their function in anti-parasite immunity. We previously reported that activation of the inflammasome in tuft cells leads to release of prostaglandin D2 (PGD2). We test the hypothesis that tuft cell specific release of PGD2 after inflammasome activation initiates antibacterial responses. NAIP--NLRC4 inflammasome activation in tuft cells leads to a type 3 antimicrobial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2 signaling. A subset of ILC3 express the PGD2 receptor CRTH2 and we show them as the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium. These data support that intestinal tuft cells can also induce antibacterial responses. SummaryPGD2 release after NAIP--NLRC4 inflammasome activation in tuft cells signals onto ILC3s and mediates host defense mechanisms against Salmonella Typhimurium within the small intestine. Tuft cells therefore not only promote immune reactions against parasites, but also bacteria.

immunology↗

bioRxiv2021

Infection-induced dermal lymphatic zippering restricts viral dissemination from skin and promotes anti-viral CD8+ T cell expansion.

Lymphatic vessels are often considered passive conduits that rapidly flush antigenic material, pathogens, and cells to draining lymph nodes. Recent evidence, however, suggests that lymphatic vessels actively regulate diverse processes from antigen transport to leukocyte trafficking and dietary lipid absorption. Here we tested the hypothesis that dermal lymphatic transport is dynamic and contributes to innate host defense during viral infection. We demonstrate that cutaneous vaccinia virus infection activates the tightening of lymphatic interendothelial junctions, termed zippering, in a VEGFA/VEGFR2-dependent manner. Both antibody-mediated blockade of VEGFA/VEGFR2 and lymphatic-specific deletion of Vegfr2 impaired lymphatic capillary zippering and increased fluid flux out of tissue. Strikingly, inhibition of lymphatic zippering allows viral dissemination to draining lymph nodes independent of dendritic cell migration and impairs CD8+ T cell priming. These data indicate that infection-induced dermal lymphatic capillary zippering is a context-dependent, active mechanism of innate host defense that limits interstitial fluid and virion flux and promotes protective, anti-viral CD8+ T cell responses. SummaryCutaneous infection with vaccinia virus induces VEGFR2-dependent dermal lymphatic capillary zippering. This tightening of lymphatic junctions exacerbates tissue edema, sequesters virus, and promotes anti-viral CD8+ T cell responses. Dermal lymphatic capillaries are therefore an active component of innate host defense.

immunology↗