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TNF signalling drives expansion of bone marrow CD4<sup>+</sup> T cells responsible for HSC exhaustion in experimental visceral leishmaniasis
Abstract
<div><p>Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150<sup>+</sup> CD34<sup>-</sup> CD48<sup>-</sup> cells) in bone marrow (BM) are quiescent, we found that during <i>Leishmania donovani</i> 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 IFNγ-sufficient but not IFNγ-deficient CD4<sup>+</sup> T cells. Using mixed BM chimeras, we established that IFNγ and TNF signalling pathways converge at the level of CD4<sup>+</sup> T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNγ<sup>+</sup>CD4<sup>+</sup> T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4<sup>+</sup> T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously.</p></div- Dataset
- Dataset
- Medicine
- Cell Biology
- Genetics
- Physiology
- Immunology
- Developmental Biology
- Cancer
- Hematology
- Infectious Diseases
- Computational Biology
- Physical Sciences not elsewhere classified
- Leishmania donovani infection
- BM
- LSK CD 150
- CD 4
- HSC
- target hematopoietic function
- leishmaniasis Visceral leishmaniasis
- T cells
- TNF
- LT-HSC
- IFN γ-deficient CD 4
- RAG 2 KO mice
- bone marrow CD 4
- IFN γ