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 naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent,...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006465&type=printable |
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| author | Ana Isabel Pinto Ana Isabel Pinto Najmeeyah Brown Olivier Preham Johannes S P Doehl Helen Ashwin Paul M Kaye |
| author_facet | Ana Isabel Pinto Ana Isabel Pinto Najmeeyah Brown Olivier Preham Johannes S P Doehl Helen Ashwin Paul M Kaye |
| author_sort | Ana Isabel Pinto |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b0c5ecbf22f146508a62c512174ef190 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2017-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-b0c5ecbf22f146508a62c512174ef1902025-08-20T03:07:20ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-07-01137e100646510.1371/journal.ppat.1006465TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis.Ana Isabel PintoAna Isabel PintoNajmeeyah BrownOlivier PrehamJohannes S P DoehlHelen AshwinPaul M KayeVisceral 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006465&type=printable |
| spellingShingle | Ana Isabel Pinto Ana Isabel Pinto Najmeeyah Brown Olivier Preham Johannes S P Doehl Helen Ashwin Paul M Kaye TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. PLoS Pathogens |
| title | TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. |
| title_full | TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. |
| title_fullStr | TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. |
| title_full_unstemmed | TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. |
| title_short | TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. |
| title_sort | tnf signalling drives expansion of bone marrow cd4 t cells responsible for hsc exhaustion in experimental visceral leishmaniasis |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006465&type=printable |
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