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An inflammatory loop established between spleen-derived myeloid cells and CD4+ T cells leads to accumulation of long-lived plasma cells that exacerbate lupus autoimmunity

ABSTRACT: Splenic long-lived plasma cells (PCs) are abnormally numerous and deleterious in systemic autoimmune diseases, yet how they accumulate remains poorly understood. We demonstrate here that a pathological role of spleen-derived CD11b+Gr-1+ myeloid cells (SPMCs) underpins the accumulation of splenic long-lived PCs in a lupus-prone model. SPMCs were a mixture of granulocytic and monocytic myeloid-derived suppressor cells (MDSCs) that were expanded and acquired proinflammatory phenotypes in situ during lupus progression. By promoting the development of IFN--secreting and follicular helper T cells, SPMCs licensed CD4+ T cells to be pathologic activators of SPMCs and PCs. SPMCs also directly promoted the survival of PCs by providing B-cell activating factor of the TNF family. The frequency of SPMCs correlated with that of splenic long-lived PCs. Depletion of CD11b+Gr-1+ cells reduced autoantibody production. Thus, our findings suggest that SPMCs expanded in situ establish a positive feedback loop with CD4+ T cells, leading to accumulation of long-lived PCs which exacerbate lupus autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE161850 | GEO | 2021/02/09

REPOSITORIES: GEO

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Project description:The gene expression of murine splenic myeloid derived suppressor cells treated with Tff2 is characterized. The motivation of the study originates in the fact that Gr1+Cd11b+ myeloid-derived suppressor cells (MDSCs), which resemble immature myeloid cells (IMCs), expand during cancer in response to inflammatory cytokines and accumulate in the spleen. MDSCs promote neoplastic progression through their suppression of anti-tumourigenic cytotoxic T-cells. MDSCs are also rapidly expanded following acute insults, but in cancer as opposed to acute inflammation, MDSCs persist. It is now recognized that a vagally-mediated, anti-inflammatory reflex arc promoting acetylcholine secretion by Cd4+ (Cd44hiSelllo) T cells, is necessary for a return to homeostasis after an acute insult. Failure of this restorative neural circuit might contribute to unabated procarcinogenic inflammation, with the chronic expansion of MDSCs driving carcinogenesis. Trefoil factor 2 (Tff2) is a secreted anti-inflammatory peptide produced by both epithelial cells and a small subset of splenic T cell. In this study, we show that splenic Tff2 is induced in vagally-modulated memory T cells to suppress the expansion of MDSCs in response to chemical and carcinogenic injury. Deletion of Tff2 interrupts this anti-inflammatory neural arc and leads to expanded MDSCs and a dramatically increased incidence of colorectal cancer. Tff2 directly suppresses proliferation of myeloid progenitors, in a large part through upregulation of cell-bound Apolipoprotein E (ApoE), which has previously been shown to suppress proliferation of haematopoietic stem and progenitor cells. The predisposition to inflammation-associated cancer can be rescued through transgenic overexpression of splenic Tff2, adenoviral transfer of Tff2 expression or transplantation of Tff2-expressing haematopoietic cells. Thus, Tff2 production in memory T cells, is regulated by the vagus nerve, plays a central role in arresting procarcinogenic MDSC proliferation, and offers a novel approach to the prevention and treatment. A. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Csf2 (n=4). B. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Tff2 and Csf2 (n=4).

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An inflammatory loop established between spleen-derived myeloid cells and CD4+ T cells leads to accumulation of long-lived plasma cells that exacerbate lupus autoimmunity

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