RESUMO
Lineage-committed αß and γδ T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vγ2+ γδ T cells is programmed intrathymically to produce IL-17 (Tγδ17 cells), however the role of the γδTCR in development of these cells remains controversial. Here we generated reporter mice for the Tγδ17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13+ progenitors. In organ culture developmental assays, Tγδ17 cells derived primarily from Sox13+ progenitors, and not from other known lymphoid progenitors. Single cell transcriptome assays of the progenitors found in TCR-deficient mice demonstrated that Tγδ17 lineage programming was independent of γδTCR. Instead, generation of the lineage committed progenitors and Tγδ17 cells was controlled by TCF1 and SOX13. Thus, T lymphocyte lineage fate can be prewired cell-intrinsically and is not necessarily specified by clonal antigen receptor signals.
Assuntos
Autoantígenos/metabolismo , Interleucina-17/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Animais , Autoantígenos/genética , Biomarcadores , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , TranscriptomaRESUMO
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
Mother and child are immunologically interconnected by mechanisms that we are only beginning to understand. During pregnancy, multiple molecular and cellular factors of maternal origin are transferred across the placenta and influence the development and function of the fetal and newborn immune system. Altered maternal immune states arising from pregnancy-associated infections or immunizations have the potential to program offspring immune function in ways that may have long-term health consequences. In this study, we review current literature on the impact of prenatal infection and vaccination on the developing immune system, highlight knowledge gaps, and look to the horizon to envision maternal interventions that could benefit both the mother and her child.
Assuntos
Vacinação , Humanos , Gravidez , Feminino , Recém-Nascido , Placenta/imunologia , Sistema Imunitário/imunologia , Complicações Infecciosas na Gravidez/imunologia , Troca Materno-Fetal/imunologia , Mães , Criança , Feto/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
BACKGROUND: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. METHODS: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). RESULTS: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. CONCLUSIONS: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.
Involvement of the muscularis propria accompanies a poorer prognosis in IBD. This study characterizes muscularis macrophage subpopulations during colitis, highlighting the loss of anti-inflammatory LYVE-1+ macrophages and inflammatory plasticity in resident CX3CR1+ macrophages, providing insights into prognostic and therapeutic targets.
RESUMO
Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood. To study the impact of mRNA vaccination on the humoral immunity of infant, we use a system serology approach to comprehensively profile antibody responses in a cohort of children ages 6 months to 5 years who were vaccinated with the mRNA-1273 COVID-19 vaccine (25 µg). Responses are compared with vaccinated adults (100 µg), in addition to naturally infected toddlers and young children. Despite their lower vaccine dose, vaccinated toddlers elicit a functional antibody response as strong as adults, with higher antibody-dependent phagocytosis compared to adults, without report of side effects. Moreover, mRNA vaccination is associated with a higher IgG3-dependent humoral profile against SARS-CoV-2 compared to natural infection, supporting that mRNA vaccination is effective at eliciting a robust antibody response in toddlers and young children.
Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Lactente , Humanos , Pré-Escolar , Vacina de mRNA-1273 contra 2019-nCoV , COVID-19/prevenção & controle , Vacinação , Imunidade Humoral , RNA Mensageiro , Anticorpos AntiviraisRESUMO
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both is unclear. We show here that lack of CTLA-4 in regulatory T cells leads to aberrant activation and expansion of conventional T cells. However, CTLA-4 expression in conventional T cells prevents aberrantly activated T cells from infiltrating and fatally damaging nonlymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell tolerance: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells prevents the harmful accumulation of self-reactive pathogenic T cells in vital organs.
Assuntos
Antígenos CD/imunologia , Autoimunidade , Tolerância Imunológica , Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Antígeno CTLA-4 , Diferenciação Celular , Movimento Celular , Fatores de Transcrição Forkhead/imunologia , Imunidade Inata , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Linfócitos T/citologiaRESUMO
Background: The COVID-19 pandemic had many psychological adverse effects due to fear and panic of infection. However social distancing and lockdown restrictions imposed to curb the spread of infection had an impact on the social life of people. The effects of this on the psychosocial health of the population were less explored area. Aim: To study the effect of the COVID-19 pandemic and lockdown on the psychosocial health of medical students. Materials and Methods: A cross-sectional observational study was conducted on medical students with the help of an online Google Form administering a questionnaire consisting of sociodemographic information; Coronavirus Social Distance Attitudes Scale and Attitude toward lockdown measure to assess favorable or opposing attitudes of participants toward social distancing and lockdown; Bergen Social Relationship Scale, Evaluation of Social System scale and Social Support Questionnaire to measure quality of social relations and social support satisfaction; and three item loneliness scale to evaluate feeling of loneliness. Results: The loneliness levels in participants were high (mean = 6.74 ± 0.79). There was a gender difference in the variables measured. Male students showed a favorable attitude toward social distancing (Positive social distance attitude scale P < 0.001, negative social distance attitude scale P < 0.001) and a better quality of social relations (Bergen Social relationship P < 0.001, evaluation of social system P < 0.001, SSQN P < 0.001, SSQS P < 0.001). However, male students scored more for loneliness as compared to females during the lockdown period (P < 0.001). Conclusion: The loneliness levels were high in medical students during the COVID-19 pandemic and lockdown and even higher in males who were considered a non-vulnerable group. So the balanced approach between preventive restriction measures and the social connectedness of the population is advised for making social distancing policies in the future.
RESUMO
SARS-CoV-2 mRNA vaccines elicit humoral responses in children that are comparable to those in adults. However, early-life T cell responses are distinct from adult ones, and questions remain about the nature and kinetics of mRNA vaccine-induced T cell responses in children. We report that Pfizer BNT162b2 mRNA vaccination elicits a significant antigen-specific CD4+ T cell response in the ≥12-year-old cohort. This response is weaker in magnitude in the 5- to 11-year-old cohort and is not improved by a higher vaccine dose (Moderna mRNA1273, 100 µg), suggesting distinct developmental programming that may underscore early-life T cell immunity. Increased effector phenotypes of antigen-specific T cells in younger children correspond with elevated anti-receptor binding domain antibody levels, albeit at the cost of memory generation. These studies highlight aspects of age-specific adaptive immune responses and the need for careful consideration of priming conditions including vaccine dose and adjuvant in the pediatric population.
Assuntos
COVID-19 , SARS-CoV-2 , Criança , Adulto , Humanos , Pré-Escolar , SARS-CoV-2/genética , Vacina BNT162 , COVID-19/prevenção & controle , Linfócitos T , RNA Mensageiro/genéticaRESUMO
Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood. To study the impact of mRNA vaccination on the humoral immunity of infant, we used a system serology approach to comprehensively profile antibody responses in a cohort of children ages 6 months to 5 years who were vaccinated with the mRNA-1273 COVID-19 vaccine (25 µg). Responses were compared with vaccinated adults (100 µg), in addition to naturally infected toddlers and young children. Despite their lower vaccine dose, vaccinated toddlers elicited a stronger functional antibody response than adults, including against variant of concerns (VOCs), without report of side effects. Moreover, mRNA vaccination was associated with a higher IgG3-dependent humoral profile against SARS-CoV-2 compared to natural infection, supporting that mRNA vaccination is effective at eliciting a robust antibody response in toddlers and young children.
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
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, 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.
Assuntos
Antígenos CD40/metabolismo , Leishmania major/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase/metabolismo , Transdução de Sinais/fisiologia , Células Th1/imunologia , Animais , Anisomicina/farmacologia , Antígenos CD40/imunologia , Células Cultivadas , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Imidazóis/farmacologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Inibidores da Síntese de Proteínas/farmacologia , Piridinas/farmacologia , Células Th1/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
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 balanced interplay between epithelial barrier, immune system, and microbiota maintains gut homeostasis, while disruption of this interplay may lead to inflammation. Paracellular permeability is governed by intercellular tight-junctions (TJs). Zonulin is, to date, the only known physiological regulator of intestinal TJs. We used a zonulin transgenic mouse (Ztm) model characterized by increased small intestinal permeability to elucidate the role of a primary impaired gut barrier on microbiome composition and/or immune profile. Ztm exhibit an altered gene expression profile of TJs in the gut compared to wild-type mice (WT): Claudin-15, Claudin-5, Jam-3, and Myosin-1C are decreased in the male duodenum whereas Claudin-15, Claudin-7, and ZO-2 are reduced in the female colon. These results are compatible with loss of gut barrier function and are paralleled by an altered microbiota composition with reduced abundance of the genus Akkermansia, known to have positive effects on gut barrier integrity and strengthening, and an increased abundance of the Rikenella genus, associated to low-grade inflammatory conditions. Immune profile analysis shows a subtly skewed distribution of immune cell subsets toward a pro-inflammatory phenotype with more IL-17 producing adaptive and innate-like T cells in Ztm. Interestingly, microbiota "normalization" involving the transfer of WT microbiota into Ztm, did not rescue the altered immune profile. Our data suggest that a primary impaired gut barrier causing an uncontrolled trafficking of microbial products leads to a latent pro-inflammatory status, with a skewed microbiota composition and immune profile that, in the presence of an environmental trigger, as we have previously described (1), might promote the onset of overt inflammation and an increased risk of chronic disease.
Assuntos
Microbioma Gastrointestinal/imunologia , Haptoglobinas/imunologia , Mucosa Intestinal/imunologia , Microbiota/imunologia , Precursores de Proteínas/imunologia , Animais , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Permeabilidade , Junções Íntimas/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
Neonates face unique challenges in the period following birth. The postnatal immune system is in the early stages of development and has a range of functional capabilities that are distinct from the mature adult immune system. Bidirectional immune-microbial interactions regulate the development of mucosal immunity and alter the composition of the microbiota, which contributes to overall host well-being. In the past few years, nutrition has been highlighted as a third element in this interaction that governs host health by modulating microbial composition and the function of the immune system. Dietary changes and imbalances can disturb the immune-microbiota homeostasis, which might alter susceptibility to several autoimmune and metabolic diseases. Major changes in cultural traditions, socioeconomic status and agriculture are affecting the nutritional status of humans worldwide, which is altering core intestinal microbial communities. This phenomenon is especially relevant to the neonatal and paediatric populations, in which the microbiota and immune system are extremely sensitive to dietary influences. In this Review, we discuss the current state of knowledge regarding early-life nutrition, its effects on the microbiota and the consequences of diet-induced perturbation of the structure of the microbial community on mucosal immunity and disease susceptibility.
Assuntos
Homeostase/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Microbiota/imunologia , Disbiose/imunologia , Humanos , Imunidade nas Mucosas , Intestinos/imunologia , Estado NutricionalRESUMO
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
Assuntos
Antígenos CD28/fisiologia , Quimiotaxia de Leucócito/genética , Proteínas Tirosina Quinases/fisiologia , Linfócitos T/fisiologia , Animais , Células CHO , Antígeno CTLA-4/genética , Células Cultivadas , Cricetinae , Cricetulus , Feminino , Homeostase/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transdução de Sinais/fisiologiaRESUMO
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.