Monocytic myeloid-derived suppressive cells mitigate over-adipogenesis of bone marrow microenvironment in aplastic anemia by inhibiting CD8+ T cells

Abstract

Aplastic anemia (AA) is a blood disorder resulted from over-activated T-cell related hematopoietic failure, with the characterization of hypocellularity and enhanced adipogenic differentiation of mesenchymal stroma cells (MSCs) in bone marrow (BM). However, little is known about the relationship between immune imbalance and polarized adipogenic abnormity of BM microenvironment in this disease entity. In the present study, we differentiated BM-MSCs into osteoblastic or adipogenic lineages to mimic the osteo-adipogenic differentiation. Activated CD8+ T cells and interferon-γ (IFN-γ) were found to stimulate adipogenesis of BM-MSCs either in vitro or in vivo of AA mouse model. Interestingly, myeloid-derived suppressive cells (MDSCs), one of the immune-regulating populations, were decreased within BM of AA mice. We found that it was not CD11b+Ly6G+Ly6C- granulocytic-MDSCs (gMDSCs) but CD11b+Ly6G-Ly6C+ monocytic-MDSCs (mMDSCs) inhibiting both T cell proliferation and IFN-γ production via inducible nitric oxide synthetase (iNOS) pathway. Single-cell RNA-sequencing (scRNA-seq) of AA- and mMDSCs-treated murine BM cells revealed that mMDSCs transfusion could reconstitute BM hematopoietic progenitors by inhibiting T cells population and signature cytokines and decreasing immature Adipo-Cxcl12-abundant reticular cells within BM. Multi-injection of mMDSCs into AA mice reduced intra-BM T cells infiltration and suppressed BM adipogenesis, which subsequently restored the intra-BM immune balance and eventually prevented pancytopenia and hypo-hematopoiesis. In conclusion, adoptive transfusion of mMDSCs might be a novel immune-regulating strategy to treat AA, accounting for not only restoring the intra-BM immune balance but also improving stroma’s multi-differentiating microenvironment.

Advances in understanding the role of dendritic cells in aplastic anaemia

“…The increased proportion of CD8 + CD27 + T cells in AA patients is reportedly related to disease severity. CD8 + CD27 + T cells present with a cytotoxic effector phenotype by elevating the proportion of perforin, leading to apoptosis in bone marrow haematopoietic cells 3,16 . Single‐cell RNA sequencing analysis of HSPCs and T cells in AA patients revealed that their CD8 + T cells had a high signal expression related to cell activation and immune response, which may be related to the increase in the number and activation of CD8 + T cells.…”

“…A pathological T cell-mediated immune response and an imbalanced proportion of immune cells are often observed in patients with AA. [1][2][3] Immunosuppressants can effectively inhibit activated T lymphocytes and promote immune balance to effectively improve haematopoietic function. 4,5 Dendritic cells (DCs) are the most effective antigenpresenting cells (APCs) in the body.…”

“…15 CD8 + T cells are the main population that induces bone marrow failure in AA mice. Qu et al 3 injected allogeneic CD4 + and CD8 + T cells into preirradiated mice and demonstrated that the bone marrow of AA mice injected with CD8 + T cells exhibited severe cell dysfunction and adipocyte accumulation.…”

“…CD8 + CD27 + T cells present with a cytotoxic effector phenotype by elevating the proportion of perforin, leading to apoptosis in bone marrow haematopoietic cells. 3,16 Singlecell RNA sequencing analysis of HSPCs and T cells in AA patients revealed that their CD8 + T cells had a high signal expression related to cell activation and immune response, which may be related to the increase in the number and activation of CD8 + T cells. In addition, CD8 + T cells can interact with HSPCs through a series of specific molecules, resulting in a decrease in HSPC number, which is consistent with the pathological immune response mediated by overactivated CD8 + T cells in AA haematopoietic destruction.…”

“…Aplastic anaemia (AA) is an autoimmune disease whose pathophysiology remains poorly understood. A pathological T cell‐mediated immune response and an imbalanced proportion of immune cells are often observed in patients with AA 1–3 . Immunosuppressants can effectively inhibit activated T lymphocytes and promote immune balance to effectively improve haematopoietic function 4,5 …”