HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.

Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-1) interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type...

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Autores principales:	Julien Villaudy, Mélanie Wencker, Nicolas Gadot, Nicolas A Gillet, Jean-Yves Scoazec, Louis Gazzolo, Markus G Manz, Charles R M Bangham, Madeleine Duc Dodon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5e8c6cb1e1de46aaad1f100085d5aa86
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spelling	oai:doaj.org-article:5e8c6cb1e1de46aaad1f100085d5aa862021-11-18T06:03:01ZHTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.1553-73661553-737410.1371/journal.ppat.1002231https://doaj.org/article/5e8c6cb1e1de46aaad1f100085d5aa862011-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21909275/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-1) interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αβ T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a "Human Immune System" (HIS) Rag2⁻/⁻γ(c)⁻/⁻ mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2⁻/⁻γc⁻/⁻ mice, mature single-positive (SP) CD4⁺ and CD8⁺ cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2⁻/⁻γ(c)⁻/⁻ animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.Julien VillaudyMélanie WenckerNicolas GadotNicolas A GilletJean-Yves ScoazecLouis GazzoloMarkus G ManzCharles R M BanghamMadeleine Duc DodonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 9, p e1002231 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Julien Villaudy Mélanie Wencker Nicolas Gadot Nicolas A Gillet Jean-Yves Scoazec Louis Gazzolo Markus G Manz Charles R M Bangham Madeleine Duc Dodon HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
description	Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-1) interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αβ T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a "Human Immune System" (HIS) Rag2⁻/⁻γ(c)⁻/⁻ mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2⁻/⁻γc⁻/⁻ mice, mature single-positive (SP) CD4⁺ and CD8⁺ cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2⁻/⁻γ(c)⁻/⁻ animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.
format	article
author	Julien Villaudy Mélanie Wencker Nicolas Gadot Nicolas A Gillet Jean-Yves Scoazec Louis Gazzolo Markus G Manz Charles R M Bangham Madeleine Duc Dodon
author_facet	Julien Villaudy Mélanie Wencker Nicolas Gadot Nicolas A Gillet Jean-Yves Scoazec Louis Gazzolo Markus G Manz Charles R M Bangham Madeleine Duc Dodon
author_sort	Julien Villaudy
title	HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
title_short	HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
title_full	HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
title_fullStr	HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
title_full_unstemmed	HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
title_sort	htlv-1 propels thymic human t cell development in "human immune system" rag2⁻/⁻ gamma c⁻/⁻ mice.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/5e8c6cb1e1de46aaad1f100085d5aa86
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HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.

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