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

• Published in: PLoS pathogens 2017-07, Vol.13 (7), p.e1006465-e1006465
• Main Authors: Pinto, Ana Isabel, Brown, Najmeeyah, Preham, Olivier, Doehl, Johannes S P, Ashwin, Helen, Kaye, Paul M
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Antigens; Bacterial infections; Biology; Biology and Life Sciences; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; CD150 antigen; CD34 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; Cell Cycle; Cell Proliferation; Cell self-renewal; Chimeras; Cytokines; Differentiation; Exhaustion; Hematology; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Immunology; Infections; Infectious diseases; Interferon; Interferon-gamma - genetics; Interferon-gamma - metabolism; Leishmania donovani - physiology; Leishmaniasis, Visceral - metabolism; Leishmaniasis, Visceral - parasitology; Leishmaniasis, Visceral - physiopathology; Lymphocytes; Lymphocytes T; Medical schools; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Parasitic diseases; RAG2 protein; Roles; Signal Transduction; Signaling; Stem cell transplantation; Stem cells; T cell receptors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Vector-borne diseases; Visceral leishmaniasis
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006465

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+ 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 IFNγ-sufficient but not IFNγ-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNγ 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 IFNγ+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.