Macrophage TNF-α licenses donor T cells in murine bone marrow failure and can be implicated in human aplastic anemia

Abstract

<jats:title>Abstract</jats:title> <jats:p>Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α−/− donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR−/− recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α−/− recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α−/− recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR−/− donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α–producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.</jats:p>

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

“…However, our data indicate that the number of Tregs in the bone marrow of AA patients is not predictive for the response to ATG therapy. Regarding MΦs, and in contrast to the study by Sun et al 44 , we found that AA patients had fewer MΦs, both of the CD68 and CD163 subtypes, than healthy controls. In an AA mouse model, MΦs produced TNF-α and through the TNF-α receptor engaged effector T cells and increased the production of IFN-γ 44 .…”

“…Recently, it was shown that macrophages (MΦs) play a central role in IFN-γ-related stem cell destruction. Specifically, they produce tumor necrosis factor-a (TNF-a), engage cytotoxic T cells, and consequently enhance the production of IFN-γ, forming an interactive loop [44][45][46] . Another important aspect involves regulatory T cells (Tregs), which are decreased in AA.…”

Pathogenesis of aplastic anemia

“…It is a negative regulator of hematopoiesis. Neal S Young et al demonstrated that TNF-α -/aplastic anemia mice were resistant to bone marrow destruction induced by allogeneic LN cell infusion and suggested that TNF-α was closely associated with apoptosis in AA [55]. In addition, studies have demonstrated that IFN-γ induces TNF-α production in mouse macrophages through IFN regulatory factors, IFN-1 and IFN-8.…”

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

“…This hypothesis coincides with recent studies in murine models of acute AA showing that TNFα, which is generated by host macrophages in response to infused T cells, accelerates immune-mediated BM destruction. 53 Reduced IL-2 expression observed in mice that receive DGKζ-deficient cells is consistent with rapid onset of activation, leading to functional decline of antigen-specific effector T cells that could result in their depletion. Exhaustion of rapidly expanding effector T cell populations is said to explain stronger antitumor effects in xenotransplanted DGKζ -/mice.…”