RESUMO
The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αß heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αß+ γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R-STAT5B signaling promotes a supraphysiological accumulation of CD8αß+ γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αß+ γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αß+ γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer.
Assuntos
Imunidade Inata , Interferon gama , Receptores de Antígenos de Linfócitos T gama-delta , Receptores de Interleucina-7 , Fator de Transcrição STAT5 , Timo , Animais , Interferon gama/metabolismo , Interferon gama/imunologia , Camundongos , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Timo/imunologia , Receptores de Interleucina-7/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/imunologia , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Antígenos CD8/metabolismo , Feminino , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Interleucina-7/metabolismoRESUMO
T-cell development ensures the formation of diverse repertoires of T-cell receptors (TCRs) that recognize a variety of antigens. Glycosylation is a major posttranslational modification present in virtually all cells, including T-lymphocytes, that regulates activity/functions. Although these structures are known to be involved in TCR-selection in DP thymocytes, it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease. Here, we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes, as well as dynamic alterations. After restricting the N-glycosylation profile of thymocytes to high-mannose structures, using specific glycoengineered mice (Rag1CreMgat1fl/fl), we showed remarkable defects in key developmental checkpoints, including ß-selection, regulatory T-cell generation and γδT-cell development, associated with increased susceptibility to colon and kidney inflammation and infection. We further demonstrated that a single N-glycan antenna (modeled in Rag1CreMgat2fl/fl mice) is the sine-qua-non condition to ensure normal development. In conclusion, we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.
Assuntos
Timócitos , Timo , Camundongos , Animais , Humanos , Glicosilação , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas de Homeodomínio/genética , PolissacarídeosRESUMO
Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
Assuntos
Subunidade alfa de Receptor de Interleucina-7/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Mutação com Ganho de Função , Heterozigoto , Homozigoto , Humanos , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Camundongos , Penetrância , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Accelerate lung repair in SARS-CoV-2 pneumonia is essential for pandemic handling. Innate lymphoid cells (ILCs) are likely players, given their role in mucosal protection and tissue homeostasis. We studied ILC subpopulations at two time points in a cohort of patients admitted in the hospital due to SARS-CoV-2 infection. COVID-19 patients with moderate/severe respiratory failure featured profound depletion of circulating ILCs at hospital admission, in agreement with overall lymphocyte depletion. However, ILCs recovered in direct correlation with lung function improvement as measured by oxygenation index and in negative association with inflammatory and lung/endothelial damage markers like RAGE. While both ILC1 and ILC2 expanded, ILC2 showed the most striking phenotype changes, with CCR10 upregulation in strong correlation with these parameters. Overall, CCR10+ ILC2 emerge as relevant contributors to SARS-CoV-2 pneumonia recovery.
Assuntos
Biomarcadores/metabolismo , COVID-19/imunologia , Pulmão/patologia , Linfócitos/imunologia , Pneumonia Viral/imunologia , Receptores CCR10/metabolismo , SARS-CoV-2/fisiologia , Adulto , Idoso , Antígenos de Neoplasias/metabolismo , Proliferação de Células , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Recuperação de Função Fisiológica , Células Th2/imunologia , Regulação para CimaRESUMO
Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/-CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.
Assuntos
Amino Açúcares/imunologia , COVID-19/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Monócitos/imunologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16- monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.
Assuntos
COVID-19/imunologia , Monócitos/imunologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Diferenciação Celular , Cuidados Críticos , Citocinas/metabolismo , Feminino , Humanos , Imunomodulação , Masculino , Pessoa de Meia-Idade , Fenótipo , Insuficiência Respiratória , Índice de Gravidade de Doença , Células Th2/imunologiaRESUMO
Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation.
Assuntos
Carcinogênese , Regulação Leucêmica da Expressão Gênica , Mutação , Proteínas de Neoplasias , Neoplasias Experimentais , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Interleucina-7 , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Interleucina-7/biossíntese , Receptores de Interleucina-7/genética , Transdução de Sinais , Timócitos/metabolismoRESUMO
T helper (Th) cells are critical players in the modulation of immune response outcomes. Activation of Th cells gives rise to various subsets of effector cells that are controlled via specialised regulatory T cells or through self-regulation via production of IL-10. However, the environmental factors that regulate IL-10 production by Th cells remain poorly understood. Here, we show that the neurotrophic factor receptor rearranged during transfection (RET) downregulates IL-10 production by Th cells from C57BL/6 mice. We found that effector Th cells express RET and that RET's neurotrophic factor partners are mainly produced by LN stromal cells, allowing context-dependent Th-cell regulation. Despite being dispensable for Th-cell homeostasis, RET controls IL-10 production in Th2 cells: RET-deficient Th cells exhibited increased IL-10 production, while triggering of Th1/2 cells with neurotrophic factors, namely glial-derived neurotrophic factor and neurturin, decreased the expression of IL-10. In agreement, the important IL-10 transcription factor Maf was upregulated in RET-deficient Th2 cells and down-regulated upon RET signalling activation by glial-derived neurotrophic factor family ligands. Thus, our study uncovers neurotrophic factors as novel regulators of Th-cell function, revealing that Th cells and neurons can be regulated by similar signals in tissue-specific responses.
Assuntos
Interleucina-10/imunologia , Neurturina/imunologia , Proteínas Proto-Oncogênicas c-ret/imunologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Animais , Interleucina-10/genética , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Knockout , Neuroglia/citologia , Neuroglia/imunologia , Neurônios/citologia , Neurônios/imunologia , Neurturina/genética , Proteínas Proto-Oncogênicas c-ret/genética , Transdução de Sinais/genética , Células Estromais/citologia , Células Estromais/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th2/citologiaRESUMO
Haematopoiesis is a developmental cascade that generates all blood cell lineages in health and disease. This process relies on quiescent haematopoietic stem cells capable of differentiating, self renewing and expanding upon physiological demand. However, the mechanisms that regulate haematopoietic stem cell homeostasis and function remain largely unknown. Here we show that the neurotrophic factor receptor RET (rearranged during transfection) drives haematopoietic stem cell survival, expansion and function. We find that haematopoietic stem cells express RET and that its neurotrophic factor partners are produced in the haematopoietic stem cell environment. Ablation of Ret leads to impaired survival and reduced numbers of haematopoietic stem cells with normal differentiation potential, but loss of cell-autonomous stress response and reconstitution potential. Strikingly, RET signals provide haematopoietic stem cells with critical Bcl2 and Bcl2l1 surviving cues, downstream of p38 mitogen-activated protein (MAP) kinase and cyclic-AMP-response element binding protein (CREB) activation. Accordingly, enforced expression of RET downstream targets, Bcl2 or Bcl2l1, is sufficient to restore the activity of Ret null progenitors in vivo. Activation of RET results in improved haematopoietic stem cell survival, expansion and in vivo transplantation efficiency. Remarkably, human cord-blood progenitor expansion and transplantation is also improved by neurotrophic factors, opening the way for exploration of RET agonists in human haematopoietic stem cell transplantation. Our work shows that neurotrophic factors are novel components of the haematopoietic stem cell microenvironment, revealing that haematopoietic stem cells and neurons are regulated by similar signals.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Animais , Sobrevivência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ativação Enzimática , Feminino , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-ret/deficiência , Proteínas Proto-Oncogênicas c-ret/genética , Transdução de Sinais , Nicho de Células-Tronco , Proteína bcl-X/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum-sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to "count" the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4(+) T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4(+) T cells and sensed by a population of CD4(+) Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4(+) T cells and the total CD4(+) T cell population. In other words, CD4(+) T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the key role of IL-2 and quorum-sensing mechanisms in CD4(+) T cell homeostasis during an immune response.
RESUMO
We here describe novel aspects of CD8(+) and CD4(+) T cell subset interactions that may be clinically relevant and provide new tools for regulating the reconstitution of the peripheral CD8(+) T cell pools in immune-deficient states. We show that the reconstitution capacity of transferred isolated naïve CD8(+) T cells and their differentiation of effector functions is limited, but both dramatically increase upon the co-transfer of CD4(+) T cells. This helper effect is complex and determined by multiple factors. It was directly correlated to the number of helper cells, required the continuous presence of the CD4(+) T cells, dependent on host antigen-presenting cells (APCs) expressing CD40 and on the formation of CD4/CD8/APC cell clusters. By comparing the recovery of (CD44(+)CD62L(high)) T(CM) and (CD44(+)CD62L(low)) T(EM) CD8(+) T cells, we found that the accumulation of T(CM) and T(EM) subsets is differentially regulated. T(CM)-cell accumulation depended mainly on type I interferons, interleukin (IL)-6, and IL-15, but was independent of CD4(+) T-cell help. In contrast, T(EM)-cell expansion was mainly determined by CD4(+) T-cell help and dependent on the expression of IL-2Rß by CD8 cells, on IL-2 produced by CD4(+) T-cells, on IL-15 and to a minor extent on IL-6.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Transdução de Sinais/imunologia , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Citocinas/metabolismo , Camundongos , Receptores CCR5/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Fatores de TempoRESUMO
Peripheral T-cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T-cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8(+) central-memory T cells (T(CM) ) and effector-memory T cells (T(EM)) pools after adoptive transfer of sorted CD8(+) T cells from naïve, T(CM) and T(EM) subsets into T-cell-deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8(+) T-cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4(+) CD25(+) Treg play a major role in the repopulation of the CD8(+) T-cell pool and that CD8(+) T-cell subsets impact on each other. In the absence of CD4(+) CD25(+) Treg, a small fraction of naïve CD8(+) T cells strongly proliferates, correlating with further expansion and differentiation of co-expanding CD8(+) T cells. CD4(+) CD25(+) Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered T(CM) and T(EM) fractions, and leading to repopulation of each pool with progeny of its own kind.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Linfopenia/imunologia , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Complexo CD3/genética , Antígenos CD4/biossíntese , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Comunicação Celular , Sobrevivência Celular/imunologia , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Linfopenia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regeneração , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Recent reports have hinted that it is possible to regenerate CD4+CD25+ regulatory T cells (Treg) from CD4+CD25- cells, a phenomenon termed conversion. We evaluated the relative contribution of this process to the Treg pool by transferring purified populations of CD4+ T cells into T cell-deficient mice. We report that conversion of CD25- cells into the CD4+CD25+Treg pool is minor if other bona fide CD25+ Tregs are present. Moreover, in the same hosts, the loss of CD25 expression by a population of Tregs also decreases in the presence of co-injected CD4+CD25- cells. Thus, the rate of exchange between CD25- and CD25+ T-cell populations is determined by the presence or absence of T-cell competitors. Our results attest for the role of competition in the contribution of different T-cell subsets for the regeneration of the peripheral CD4+ T-cell pool during lymphopenia.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Animais , Separação Celular/métodos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
To fulfill its mission, the immune system must maintain a complete set of different cellular subpopulations that play specific roles in immune responses. We have investigated the mechanisms regulating CD4+CD25+ regulatory T (Treg) cell homeostasis. We show that the expression of the high-affinity IL-2Ralpha endows these cells with the capacity to explore the IL-2 resource, ensuring their presence while keeping their number tied to the number of CD4+ T cells that produce IL-2. We show that such a homeostatic mechanism allows the increased expansion of T cells without causing disease. The indexing of Treg cells to the number of activated IL-2-producing cells may constitute a feedback mechanism that controls T cell expansion during immune responses, thus preventing autoimmune or lymphoproliferative diseases. The present study highlights that maintenance of proportions between different lymphocyte subsets may also be critical for the immune system and are under strict homeostatic control.
Assuntos
Contagem de Linfócito CD4 , Homeostase/imunologia , Interleucina-2/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/citologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Sobrevivência Celular/imunologia , Fatores de Transcrição Forkhead/biossíntese , Memória Imunológica , Interleucina-2/fisiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplanteRESUMO
A system under homeostatic control tends to maintain its structure and functions by establishing dynamic equilibriums controlled by multiple regulatory mechanisms. We have shown that this is the case for immune system. Several different mechanisms seem to participate in the homeostatic control of T cell numbers and population distribution. In other words, besides a quantitative dimension, there is also a qualitative dimension in T cell homeostasis. This is achieved through competition by driving the specialization of sub-populations of lymphocytes to occupy specific niches in the peripheral pool and by developing independent homeostatic mechanisms for each particular cell sub-set. Thus, the sizes of the naïve and memory T cell compartments are governed by independent homeostatic mechanisms, which preserve the capacity to deal with any novel infection (conferred by the presence of naïve T cells) whilst ensuring the efficacy of memory responses when dealing with recurring antigens. Peripheral T cell homeostasis also depends on the integrity of sub-population structure and the presence of regulatory CD4+ CD25+ T cells. The indexation of regulatory CD4+ CD25+ T cell numbers to the numbers of peripheral activated CD4+ T cells is another mechanism of homeostasis that has major advantages in the control of immune responses. It ensures continuous regulation of T cell numbers throughout immune responses, allowing for increases in cell numbers as long as the proportion of CD4+ CD25+ regulatory T cells is kept.
Assuntos
Regulação da Expressão Gênica , Homeostase/imunologia , Linfócitos T/imunologia , Linfócitos T/fisiologia , Timo/citologia , Animais , Humanos , Memória Imunológica , Contagem de Linfócitos , Camundongos , Timo/imunologiaRESUMO
We show that the lymphoid hyperplasia observed in IL-2Ralpha- and IL-2-deficient mice is due to the lack of a population of regulatory cells essential for CD4 T cell homeostasis. In chimeras reconstituted with bone marrow cells from IL-2Ralpha-deficient donors, restitution of a population of CD25(+)CD4(+) T cells prevents the chaotic accumulation of lymphoid cells, and rescues the mice from autoimmune disease and death. The reintroduction of IL-2-producing cells in IL-2-deficient chimeras establishes a population of CD25(+)CD4(+) T cells, and restores the peripheral lymphoid compartments to normal. The CD25(+)CD4(+) T cells regulated selectively the number of naive CD4(+) T cells transferred into T cell-deficient hosts. The CD25(+)CD4(+)/naive CD4 T cell ratio and the sequence of cell transfer determines the homeostatic plateau of CD4(+) T cells. Overall, our findings demonstrate that IL-2Ralpha is an absolute requirement for the development of the regulatory CD25(+)CD4(+) T cells that control peripheral CD4 T cell homeostasis, while IL-2 is required for establishing a sizeable population of these cells in the peripheral pools.