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Crosstalk between murine marginal zone B cells, macrophages and CD8alpha+ dendritic cells promotes Listeria monocytogenes infection

ABSTRACT: Type 1 CD8α+ conventional dendritic cells (cDC1s) harbor and transport Listeria monocytogenes (LM) within the spleen and thereby promote infection; cDC1s are also required for CD8+ T cell priming. To test the role of the second lineage of splenic cDC in regulating infection or adaptive immunity to LM we used Dock8-deficient mice, which have impaired 33D1+ type 2 cDC (cDC2) function. We found reduced CD8+ T cell activation in Dock8-deficient mice, but this was not due to impaired cDC2 function but rather resistance to LM infection. Bacterial resistance was due to loss of marginal zone B (MZB) cells. We showed that IL-10 production by MZB cells did not alter antigen handling pathways in dendritic cells (DCs), including ones relevant for cross-priming or Listeria survival. Instead, IL-10 increased intracellular LM in macrophages in the marginal zone, which transfer bacteria to cDC1s. Bacteria-harboring cDC1s then traffic into the splenic white pulp where protection from sterilizing phagocytes promotes LM expansion. This work uncovers a unique crosstalk between the innate immune cells in the marginal zone, facilitated by IL-10, that promotes both infection but also CD8+ T cell activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE124771 | GEO | 2019/06/20

REPOSITORIES: GEO

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Project description:Tumors and chronic infections result in sustained antigen exposure, which promotes impaired functional responsiveness in T cells referred to as exhaustion. Checkpoint immunotherapy can induce the reinvigoration of cellular immunity by activating a recently identified precursor of exhausted T (TPEX) cell population. This activation requires cellular interactions between TPEX cells and professional antigen-presenting cells, likely conventional dendritic cells (cDC). Currently, it is unknown where cDC - TPEX cell interactions take place and which cDC subsets are involved. To address these questions, we first mapped the differentiation trajectory of TPEX cell subsets via transitory cellular states towards terminally exhausted T (TEX) cells, identified transcriptionally distinct subpopulations and defined their localization in the spleen during chronic viral infection. We found that cDC were required for TPEX cell proliferation, differentiation and viral control during PD-L1 treatment. In particular cDC1, a specialized subset of dendritic cells, colocalized with TPEX cells and regulated their maintenance by promoting the functionality of stromal cells that support TPEX cell survival. Additionally, during PD-L1 treatment, the splenic cDC1 network was significantly reorganized at the marginal zone, a site of TPEX cell differentiation. As a consequence, viral control during checkpoint immunotherapy and cellular integrity of the marginal zone depended on the presence of cDC1. Since cDC2 were sufficient to drive initial TPEX cell proliferation and TEX cell generation but not viral control, our data suggest a new concept in which cDC1 decelerate the speed of differentiation of TPEX cells via transitory cellular states and thereby generate a therapeutic window for effective immunotherapy. Together, our findings reveal how the dynamic spatial organization of the DC network supports cellular niches that guide the maintenance and differentiation of TPEX cells and opens new avenues to optimize checkpoint immunotherapy.

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Crosstalk between murine marginal zone B cells, macrophages and CD8alpha+ dendritic cells promotes Listeria monocytogenes infection

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