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This work was supported by the Instituto Gulbenkian de Ciencia (IGC)-Fundacao Calouste Gulbenkian, by the Portuguese National Research Council (Fundacao para a Ciencia e Tecnologia [FCT], Grant PTDC/BIA-BID/30925/2017) (to V.C.M.). R.A.P. is a Ph.D. student of the IGC Integrative Biology and Biomedicine Ph.D. Program and is supported by an individual Ph.D. fellowship from the FCT (PD/BD/114341/2016). This work was developed with the support of the research infrastructure Congento, Project Grant LISBOA-01-0145-FEDER-022170, and ONEIDA project Grant LISBOA-01-0145-FEDER-016417, both cofinanced by Lisboa Regional Operational Programme (Lisboa 2020) under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund and FCT.

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T Cell Acute Lymphoblastic Leukemia as a Consequence of Thymus Autonomy

Publicat a:Journal Of Immunology. 202 (4): 1137-1144 - 2019-02-15 202(4), DOI: 10.4049/jimmunol.1801373

Autors: Ballesteros-Arias, Luna; Silva, Joana G; Paiva, Rafael A; Carbonetto, Belen; Faisca, Pedro; Martins, Vera C

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Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to T-ALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2(-/-) gamma(-/-)(c), gamma(-/-)(c), Rag2(-/-) IL-7r alpha(-/-), and IL-7r alpha(-/-). We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7r alpha(-/-) versus gamma(-/-)(c) Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of T-ALL. In all tested conditions, T-ALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of T-ALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of T-ALL. We found no influence for T-ALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains.

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