cDC1 coordinate innate and adaptive responses in the omentum required for T cell priming and memory

Abstract

In the peritoneal cavity, the omentum contains fat-associated lymphoid clusters (FALCs) whose role in response to infection is poorly understood. After intraperitoneal immunization with Toxoplasma gondii , conventional type 1 dendritic cells (cDC1s) were critical to induce innate sources of IFN-γ and cellular changes in the FALCs. Unexpectedly, infected peritoneal macrophages that migrated into the FALCs primed CD8 + T cells. Although T cell priming was cDC1 independent, these DCs were required for maximal CD8 + T cell expansion. An agent-based computational model and experimental data highlighted that cDC1s affected the magnitude of the proliferative burst and promoted CD8 + T cell expression of nutrient uptake receptors and cell survival. Thus, although FALCs lack the organization of secondary lymphoid organs, cDC1s resident in this tissue coordinate innate responses to microbial challenge and provide secondary signals required for T cell expansion and memory formation.

PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis

“…To directly assess whether the enhanced eT reg cell populations observed after blockade of PD-L1 and/or CTLA-4 at homeostasis would impact the ability to generate de novo T cell responses, these pathways were blocked in naïve mice that were then immunized with a non-replicative form of Toxoplasma gondii that expresses OVA. This vaccine strain provides a system to assess the activities required to generate effector T cell responses ( 42 , 49 ). In these studies, mice were treated with isotype, α-PD-L1 or α-CTLA-4 and three days later were recipients of OTI T cells.…”

“…After 24 hours following the transfer of OTI cells, we intraperitoneally vaccinated these mice with 200,000 tachyzoites of a non-replicating vaccination-strain of T. gondii that expresses OVA (CPS-OVA). Previous studies have shown that CPS alone does not lead to activation of OTI or P14 TCR transgenic CD8 + T cells, and expression of OVA is essential for activation and expansion of the OTI T cells ( 42 ). At 24 hours after vaccination, we re-dosed these groups of mice with the original blocking antibody they had previously received to maintain the blockade treatment.…”

Early T-bet promotes LFA1 upregulation required for CD8+ effector and memory T cell development

“…Because the omentum is the site of T cell priming after i.p. injection of antigens ( Carlow et al, 2009 ; Rangel-Moreno et al, 2009 ; Christian et al, 2020 ), we examined the T cell response in this tissue using CD69 as a marker of TCR engagement combined with Ki67 as a marker of cells entering cell cycle ( Eickhoff et al, 2015 ; Feng et al, 2005 ; Gerner et al, 2017 ; Testi et al, 1989 ). In unimmunized mice, 5–10% of CD8 + T cells in the omentum displayed low basal levels of CD69 ( Fig.…”

Intestinal cDC1s provide IL-12 dependent and independent functions required for CD4+T cell-mediated resistance toCryptosporidium

“…One possible explanation that might influence the degree of Th1 commitment in CD4 + T cells after priming is whether the pathogen is restricted to a barrier site like the gut, skin, or lungs, or is one that disseminates more widely. For systemic pathogens like Toxoplasma gondii , parasite dissemination leads to the early presence of parasites in lymphoid tissues and local production of IL-12 that results in the rapid commitment to the Th1 phenotype (58,62). When this occurs following oral infection with T. gondii , these heightened CD4 + T cell responses can result in an IFN-γ-mediated lethal ileitis (63).…”