ABSTRACT
CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Proliferation , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , Anti-Bacterial Agents/pharmacology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/microbiology , CD4-Positive T-Lymphocytes/transplantation , Cell Proliferation/drug effects , Cells, Cultured , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Genotype , Homeostasis , Host-Pathogen Interactions , Inflammation/immunology , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Microbiota/immunology , Phenotype , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/microbiology , T-Lymphocytes, Regulatory/transplantation , Time FactorsABSTRACT
Ouabain (OUA) is an endogenous hormone released by the adrenal gland under stress situations. Steroid hormones and glucocorticoids have been characterized as selective inhibitors of lymphopoiesis. The present report shows in vivo modulation of mature B cells in bone marrow, spleen and peripheral blood by ouabain. Mice injected intraperitonially (i.p.) with ouabain 0.56 mg/kg for 3 consecutive days displayed, 24 h after last injection, a decreased cellularity in the bone marrow with diminution of the mature B cell subpopulation while the other B cell subpopulations were preserved. Percentually, the myeloid lineage in bone marrow was increased by ouabain. Numbers of mature B lymphocytes in spleen and peripheral blood were reduced following in vivo treatment. In vitro, the B cell populations were not affected. The effects appear to be independent of steroid hormones and strain. The presence of stable levels of glucocorticoids seems to be important because the effects could only be observed from the fourth week animal's life, when glucocorticoid levels are stable. These results open new perspectives for a potential use of ouabain as an immunomodulator.
