TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis.

Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naive mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150(+) CD34(-) CD48(-) cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFN gamma-sufficient but not IFN gamma-deficient CD4(+) T cells. Using mixed BM chimeras, we established that IFN gamma and TNF signalling pathways converge at the level of CD4(+) T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFN gamma(+)CD4(+) T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4(+) T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously.