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

Abstract

Interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) 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-g produced by donor T cells and the IFN-g receptor in the host in murine immune-mediated BM failure models. TNF-a has been assumed to function similarly to IFN-g. We used our murine models and mice genetically deficient in TNF-a or TNF-a receptors (TNF-aRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-a2/2 donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-aR2/2 recipients both induced BM failure, with concurrent marked increases in plasma IFN-g and TNF-a levels. Surprisingly, in TNF-a2/2 recipients, BM damage was attenuated, suggesting that TNF-a of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-g levels and reduced BM damage, whereas injection of recombinant TNF-a into FVB-LN cell-infused TNF-a2/2 recipients increased T-cell IFN-g expression and accelerated BM damage. Furthermore, infusion of TNF-aR2/2 donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-g production, and alleviated BM destruction. Thus, TNF-a from host macrophages andTNF-aRexpressedondonoreffectorTcellswerecriticalinthepathogenesisofmurineimmune-mediatedBMfailure,acting by modulation of IFN-g secretion. In AA patients, TNF-a–producing macrophages in the BM were more frequent than in healthycontrols,suggestingtheinvolvementofthiscytokineandthesecellsinhumandisease.