RESUMO
Resident tissue macrophages (RTMs) develop from distinct waves of embryonic progenitor cells that seed tissues before birth. Tissue-specific signals drive a differentiation program that leads to the functional specialization of RTM subsets. Genetic programs that regulate the development of RTMs are incompletely understood, as are the mechanisms that enable their maintenance in adulthood. In this study, we show that the ligand-activated nuclear hormone receptor, retinoid X receptor (RXR)α, is a key regulator of murine RTM development. Deletion of RXRα in hematopoietic precursors severely curtailed RTM populations in adult tissues, including the spleen, peritoneal cavity, lung, and liver. The deficiency could be traced to the embryonic period, and mice lacking RXRα in hematopoietic lineages had greatly reduced numbers of yolk sac and fetal liver macrophages, a paucity that persisted into the immediate postnatal period.
Assuntos
Macrófagos , Saco Vitelino , Animais , Diferenciação Celular/fisiologia , Fígado , Camundongos , BaçoRESUMO
The early life immune system is characterized by unique developmental milestones. Functionally diverse immune cells arise from distinct waves of hematopoietic stem cells, a phenomenon referred to as 'layered' immunity. This stratified development of immune cells extends to lineages of both innate and adaptive cells. The defined time window for the development of these immune cells lends itself to the influence of specific exposures typical of the early life period. The perinatal immune system develops in a relatively sterile fetal environment but emerges into one filled with a multitude of antigenic encounters. A major burden of this comes in the form of the microbiota that is being newly established at mucosal surfaces of the newborn. Accumulating evidence suggests that early life microbial exposures, including those arising in utero, can imprint long-lasting changes in the offspring's immune system and determine disease risk throughout life. In this review, I highlight unique features of early life immunity and explore the role of intestinal bacteria in educating the developing immune system.
Assuntos
Microbioma Gastrointestinal , Sistema Imunitário/crescimento & desenvolvimento , Sistema Imunitário/imunologia , Animais , Feminino , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Assistência Perinatal , GravidezRESUMO
The thymus generates cells of the T cell lineage that seed the lymphatic and blood systems. Transcription factor regulatory networks control the lineage programming and maturation of thymic precursor cells. Whether extrathymic antigenic events, such as the microbial colonization of the mucosal tract also shape the thymic T cell repertoire is unclear. We show here that intestinal microbes influence the thymic homeostasis of PLZF-expressing cells in early life. Impaired thymic development of PLZF+ innate lymphocytes in germ-free (GF) neonatal mice is restored by colonization with a human commensal, Bacteroides fragilis, but not with a polysaccharide A (PSA) deficient isogenic strain. Plasmacytoid dendritic cells influenced by microbes migrate from the colon to the thymus in early life to regulate PLZF+ cell homeostasis. Importantly, perturbations in thymic PLZF+ cells brought about by alterations in early gut microbiota persist into adulthood and are associated with increased susceptibility to experimental colitis. Our studies identify a pathway of communication between intestinal microbes and thymic lymphocytes in the neonatal period that can modulate host susceptibility to immune-mediated diseases later in life.
Assuntos
Microbioma Gastrointestinal , Linfócitos/imunologia , Timo/crescimento & desenvolvimento , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bacteroides fragilis/fisiologia , Diferenciação Celular , Colite/genética , Colite/imunologia , Colite/microbiologia , Colo/microbiologia , Humanos , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Timo/citologia , Timo/imunologiaRESUMO
Enteric bacterial communities are established early in life and influence immune cell development and function. The neonatal microbiota is susceptible to numerous external influences including antibiotics use and diet, which impacts susceptibility to autoimmune and inflammatory diseases. Disorders such as Inflammatory Bowel Disease (IBD) are characterized by a massive influx of immune cells to the intestines. However, immune cells conditioned by the microbiota may additionally emigrate out of the intestines to influence immune responses at extra-intestinal sites. Thus, there is a need to identify and characterize cells that may carry microbial messages from the intestines to distal sites. Here, we describe a method to label cells in the colon of newborn mice in vivo that enables their identification at extra-intestinal sites after migration.
Assuntos
Colo/citologia , Hematopoese/genética , Animais , Colo/metabolismo , Humanos , Recém-Nascido , CamundongosRESUMO
FOXP3-expressing regulatory T (Treg) cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. In this study we show that in mouse peripheral lymphocytes the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFbeta responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3, and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed, and DAB2 appears to be dispensable for Treg cell function in maintaining naive T cell homeostasis.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Animais , Proteínas Reguladoras de Apoptose , Comunicação Celular/genética , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Fatores de Transcrição Forkhead/metabolismo , Junções Comunicantes/genética , Junções Comunicantes/imunologia , Homeostase/genética , Homeostase/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T Reguladores/citologiaRESUMO
Leishmania donovani, a protozoan parasite, inflicts a fatal disease, visceral leishmaniasis. The suppression of antileishmanial T cell responses that characterizes the disease was proposed to be due to deficiency of a T cell growth factor, IL-2. We demonstrate that during the first week after L. donovani infection, IL-2 induces IL-10 that suppresses the host-protective functions of T cells 14 days after infection. The observed suppression is concurrent with increased CD4+ glucocorticoid-induced TNF receptor+ T cells and Foxp3 expression in BALB/c mice, implicating IL-2-dependent regulatory T cell control of antileishmanial immune responses. Indeed, IL-2 and IL-10 neutralization at different time points after the infection demonstrates their distinct roles at the priming and effector phases, respectively, and establishes kinetic modulation of ongoing immune responses as a principle of a rational, phase-specific immunotherapy.
Assuntos
Imunoterapia , Interleucina-10/biossíntese , Interleucina-2/metabolismo , Leishmaniose Visceral/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD4/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Interleucina-2/administração & dosagem , Leishmania donovani/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-2/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-gamma, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major-infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major-infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance.