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1.
Int Immunol ; 30(4): 155-169, 2018 04 03.
Article in English | MEDLINE | ID: mdl-29420746

ABSTRACT

The incidence of allergic diseases, which increased to epidemic proportions in developed countries over the last few decades, has been correlated with altered gut microbiota colonization. Although probiotics may play a critical role in the restoration of gut homeostasis, their efficiency in the control of allergy is controversial. Here, we aimed to investigate the effects of probiotic treatment initiated at neonatal or adult ages on the suppression of experimental ovalbumin (OVA)-induced asthma. Neonatal or adult mice were orally treated with probiotic bacteria and subjected to OVA-induced allergy. Asthma-like symptoms, microbiota composition and frequencies of the total CD4+ T lymphocytes and CD4+Foxp3+ regulatory T (Treg) cells were evaluated in both groups. Probiotic administration to neonates, but not to adults, was necessary and sufficient for the absolute prevention of experimental allergen-induced sensitization. The neonatally acquired tolerance, transferrable to probiotic-untreated adult recipients by splenic cells from tolerant donors, was associated with modulation of gut bacterial composition, augmented levels of cecum butyrate and selective accumulation of Treg cells in the airways. Our findings reveal that a cross-talk between a healthy microbiota and qualitative features inherent to neonatal T cells, especially in the Treg cell subset, might support the beneficial effect of perinatal exposure to probiotic bacteria on the development of long-term tolerance to allergens.


Subject(s)
Asthma/etiology , Asthma/prevention & control , Immunomodulation , Microbiota , Probiotics/administration & dosage , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Adult , Allergens/immunology , Animals , Antigens/immunology , Asthma/diagnosis , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Infant, Newborn , Mice , Pregnancy
2.
Elife ; 62017 09 12.
Article in English | MEDLINE | ID: mdl-28895840

ABSTRACT

MyD88 is the main adaptor molecule for TLR and IL-1R family members. Here, we demonstrated that T-cell intrinsic MyD88 signaling is required for proliferation, protection from apoptosis and expression of activation/memory genes during infection with the intracellular parasite Trypanosoma cruzi, as evidenced by transcriptome and cytometry analyses in mixed bone-marrow (BM) chimeras. The lack of direct IL-18R signaling in T cells, but not of IL-1R, phenocopied the absence of the MyD88 pathway, indicating that IL-18R is a critical MyD88-upstream pathway involved in the establishment of the Th1 response against an in vivo infection, a presently controvert subject. Accordingly, Il18r1-/- mice display lower levels of Th1 cells and are highly susceptible to infection, but can be rescued from mortality by the adoptive transfer of WT CD4+ T cells. Our findings establish the T-cell intrinsic IL-18R/MyD88 pathway as a crucial element for induction of cognate Th1 responses against an important human pathogen.


Subject(s)
Chagas Disease/immunology , Interleukin-18 Receptor alpha Subunit/metabolism , Myeloid Differentiation Factor 88/metabolism , Signal Transduction , Th1 Cells/immunology , Th1 Cells/parasitology , Trypanosoma cruzi/immunology , Adoptive Transfer , Animals , Chagas Disease/therapy , Disease Models, Animal , Flow Cytometry , Gene Expression Profiling , Mice, Inbred C57BL , Mice, Knockout , Survival Analysis
3.
Immun Inflamm Dis ; 4(4): 474-486, 2016 12.
Article in English | MEDLINE | ID: mdl-27980781

ABSTRACT

INTRODUCTION: A tight balance between regulatory CD4+Foxp3+ (Treg) and conventional CD4+Foxp3- (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self-tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment. METHODS: We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Additionally, lymphoid cells from young and aged B6 mice were intravenously transferred to B6.RAG2-/- mice. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days by flow cytometry. RESULTS: Thymectomized young mice presented a progressive increase in the Treg cell frequency, while the grafting of a functional thymus in aged mice restored the young-like physiological Treg/Tconv proportion. Strikingly, T cells derived from young or aged splenocytes colonized the lymphopenic periphery of RAG-/- hosts to the same extent, giving rise to similarly elevated Treg cell levels irrespective of the age of the donor population. In the absence of thymus output, the Treg subset seems to survive longer, as confirmed by their lower proportion of Annexin-V+ cells. CONCLUSIONS: Our data suggest that the thymus-emigrating population, harboring an adequate proportion of Treg/Tconv lymphocytes, may be essential to keep the Treg cell balance, independently of age-related shifts intrinsic to the peripheral environment or to the T cell biology.


Subject(s)
Homeostasis , T-Lymphocyte Subsets , T-Lymphocytes, Regulatory/physiology , Thymus Gland/physiology , Animals , Immune Tolerance , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Self Tolerance
4.
Sci Rep ; 6: 28573, 2016 06 29.
Article in English | MEDLINE | ID: mdl-27353032

ABSTRACT

Intestinal inflammation can be induced by the reconstitution of T/B cell-deficient mice with low numbers of CD4(+) T lymphocytes depleted of CD25(+)Foxp3(+) regulatory T cells (Treg). Using RAG-knockout mice as recipients of either splenocytes exclusively depleted of CD25(+) cells or FACS-purified CD4(+)CD25(-)Foxp3(-) T cells, we found that the augmentation of potentially colitogenic naïve T cell numbers in the inoculum was unexpectedly beneficial for the suppression of colon disease and maintenance of immune homeostasis. Protection against T cell-mediated colitis correlated with a significant increment in the frequency of peripherally-induced CD4(+)CD25(+)Foxp3(+) T (pTreg) cells, especially in the mesenteric lymph nodes, an effect that required the presence of B cells and CD4(+)CD25(-)Foxp3(+) cells in physiological proportions. Our findings support a model whereby the interplay between B lymphocytes and a diversified naïve T cell repertoire is critical for the generation of CD4(+)CD25(+)Foxp3(+) pTreg cells and colitis suppression.


Subject(s)
B-Lymphocytes/immunology , Colitis/immunology , Colitis/prevention & control , Models, Immunological , T-Lymphocytes, Regulatory/immunology , Animals , B-Lymphocytes/pathology , Colitis/genetics , Colitis/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Mesentery/immunology , Mesentery/pathology , Mice , Mice, Knockout , T-Lymphocytes, Regulatory/pathology
5.
Immunology ; 147(2): 221-39, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26572097

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 Factors
6.
Immunobiology ; 216(9): 1038-43, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21514687

ABSTRACT

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.


Subject(s)
B-Lymphocytes/drug effects , Bone Marrow/drug effects , Cell Differentiation/drug effects , Cell Lineage/drug effects , Lymphopoiesis/drug effects , Ouabain/pharmacology , Spleen/drug effects , Animals , Antigens, CD/immunology , B-Lymphocytes/immunology , Bone Marrow/immunology , Cell Differentiation/immunology , Cell Lineage/immunology , Cells, Cultured , Female , Flow Cytometry , Glucocorticoids/immunology , Glucocorticoids/pharmacology , Immunologic Factors/pharmacology , Injections, Intraperitoneal , Lymphopoiesis/immunology , Male , Mice , Mice, Inbred C57BL , Ouabain/immunology , Spleen/immunology
7.
Immunology ; 125(3): 387-96, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18462348

ABSTRACT

We studied the tolerization of neonatal thymocytes (NT), neonatal splenocytes (NS) and adult thymocytes (AT), transferred to syngeneic nude (nu/nu) hosts previously injected with semi-allogeneic splenocytes, without any supportive immunosuppressive treatment. This protocol allows the study of peripheral tolerance in the absence of the thymus. BALB/c neonatal T cells and ATs were able to expand in syngeneic BALB/c nu/nu mice and functionally reconstituted an allogeneic response, rejecting (BALB/c x B6.Ba) F1 splenocytes transferred 3-4 weeks after injection of BALB/c cells. However, if (BALB/c x B6.Ba) F1 cells were injected into BALB/c nude hosts 30 days before transfer of NT, NS or AT cells, the F1 population was preserved and specific tolerance to B6 allografts was established. Furthermore, transfer to lymphopenic F1 nu/nu showed that tolerance could be established only for neonatal populations, showing that unique properties of neonatal T cells allow their tolerization in both lymphopenic and non-lymphopenic conditions, in the absence of suppressive immunotherapy. These results bring empirical support to the possibility of T-cell engraftment in immunodeficient patients showing partial identity with donor major histocompatibility complex (MHC) genes; the manipulation of immunological maturity of donor T cells may be the key for successful reconstitution of immunocompetence without induction of graft-versus-host disease.


Subject(s)
Immune Tolerance/immunology , T-Lymphocytes, Regulatory/immunology , Thymus Gland/immunology , Aging/immunology , Animals , Animals, Newborn , Female , Lymphocyte Transfusion , Lymphopenia/immunology , Mice , Mice, Inbred Strains , Mice, Nude , Skin Transplantation/immunology , Spleen/immunology , Spleen/transplantation , Thymus Gland/transplantation
8.
J Immunol ; 176(4): 2324-9, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16455989

ABSTRACT

We show in this study that long-term tolerance to allogeneic skin grafts can be established in the absence of immunosuppression by the combination of the following elements: 1) augmenting the frequency of regulatory CD4(+)CD25(+) T cells (Treg) and 2) presentation of the allogeneic stimuli through linked recognition of allo- and self-epitopes on semiallogeneic F(1) APCs. BALB/c spleen cells enriched for CD4(+)CD25(+) T lymphocytes were transferred either to BALB/c nu/nu mice or to BALB/c nu/nu previously injected with F(1)(BALB/c x B6.Ba) spleen cells, or else grafted with F(1)(BALB/c x B6.Ba) skin (chimeric BALB/c nu/nu-F(1)). Chimeric BALB/c nu/nu-F(1) reconstituted with syngeneic CD25(+)-enriched spleen cells were unable to reject the previously transferred F(1)(BALB/c x B6.Ba) spleen cells or F(1)(BALB/c x B6.Ba) skin grafts, and a specific tolerance to a secondary B6 graft was obtained, with rejection of third-party CBA grafts. BALB/c nu/nu mice reconstituted only with syngeneic CD25(+)-enriched spleen cells rejected both B6 and CBA skin grafts. In contrast, when chimeric BALB/c nu/nu-F(1) were reconstituted with spleen populations comprising normal frequencies of Treg cells, the linked recognition of allo and self resulted in breaking of self tolerance and rejection of syngeneic grafts, strongly suggesting that linked recognition works in both directions, either to establish tolerance to allo, or to break tolerance to self, the critical parameter being the relative number of Treg cells.


Subject(s)
Autoantigens/immunology , CD4-Positive T-Lymphocytes/immunology , Histocompatibility Antigens/immunology , Immune Tolerance/immunology , Isoantigens/immunology , Receptors, Interleukin-2/immunology , Animals , Graft Survival/immunology , Mice , Phenotype , Skin Transplantation/immunology , Spleen/immunology , Transplantation, Homologous/immunology
9.
Immunobiology ; 207(5): 339-49, 2003.
Article in English | MEDLINE | ID: mdl-14575149

ABSTRACT

We studied extrathymic lymphocyte populations expanded in nude mice after allogeneic stimuli. These were either cells from different tissues or Immunoglobulin (Ig). Although the cells transferred, obtained from Thy-1.1+ donors, were able to induce similar increase in the nude host Thy-1.2+ population, the expanded populations could be qualitatively distinguished from each other by their different expression of mature T cell molecules and by their functional profile. The extrathymic lymphocytes expanded in animals receiving allogeneic fetal thymocytes (FT) were preferentially CD4+ cells and could confer a functional immunocompetent system to the nude host, able to reject allogeneic skin grafts. In contrast, allogeneic adult red blood cells (RBC) led to the expansion of a CD8+ population and to an auto-reactive profile, resulting in the rejection of syngeneic skin grafts by most of the nude hosts. Neither of these profiles was achieved with the other stimuli. These findings support the view that different activation pathways and/or regulatory interactions may lead to the development of distinct extrathymic populations.


Subject(s)
T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Thymus Gland/cytology , Animals , Cell Division/drug effects , Cells, Cultured , Erythrocyte Transfusion , Graft vs Host Disease , Hepatocytes/cytology , Hepatocytes/transplantation , Immunoglobulins , Lymph Nodes/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Skin Transplantation/immunology , Spleen/immunology , T-Lymphocytes/immunology , Thymus Gland/embryology , Thymus Gland/immunology , Thymus Gland/transplantation
10.
Immunobiology ; 207(3): 207-15, 2003.
Article in English | MEDLINE | ID: mdl-12777062

ABSTRACT

The functional immunological reconstitution and the patterns of cytokine secretion were comparatively studied in BALB/c nu/nu mice grafted with allogeneic B6.Thy-1.1+ E14 or E18 embryonic thymus. In spite of equivalent proliferative responses to both mitogen or MLR stimuli, the two groups presented different cytokine patterns. B6 E18-thymus grafted BALB/c nu/nu mice showed a predominant IL-2/IFN-gamma secretion in response to mitogen or to CBA haplotype, with insignificant secretion of either cytokine to the tolerated BALB/c or donor B6 haplotype. In contrast, E14 grafted mice showed a significant IL-10 secretion, both in response to mitogens or to the tolerated haplotypes, even in the absence of a detectable proliferative response. A significant IFN-gamma secretion appeared only accompanying high responses to CBA. The preferential Th2 profile associated to the E14 chimeras was coincident with a longer lifespan of the nude host kept in a conventional environment, higher CD3+ cells frequency in the blood and functional restoration of allogeneic skin graft rejection, not seen on the E18 chimeras. The meaning of these results is discussed in relation to the previously described longer persistence of the first-wave donor derived lymphocytes in the allogeneic BALB/c periphery, also exclusive of the E14 grafted group.


Subject(s)
T-Lymphocytes/immunology , Animals , Antigen-Presenting Cells , CD3 Complex/biosynthesis , Cell Division , Cell Separation , Cytokines/biosynthesis , Flow Cytometry , Haplotypes , Interferon-gamma/metabolism , Interleukin-10/metabolism , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Nude , Skin Transplantation/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/physiology , Th2 Cells , Thymus Gland/embryology , Thymus Gland/metabolism , Time Factors , Transplantation, Homologous
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