RESUMO
Intrathymic T cell development is a complex process that depends upon continuous guidance from thymus stromal cell microenvironments. The thymic epithelium within the thymic stroma comprises highly specialized cells with a high degree of anatomic, phenotypic, and functional heterogeneity. These properties are collectively required to bias thymocyte development toward production of self-tolerant and functionally competent T cells. The importance of thymic epithelial cells (TECs) is evidenced by clear links between their dysfunction and multiple diseases where autoimmunity and immunodeficiency are major components. Consequently, TECs are an attractive target for cell therapies to restore effective immune system function. The pathways and molecular regulators that control TEC development are becoming clearer, as are their influences on particular stages of T cell development. Here, we review both historical and the most recent advances in our understanding of the cellular and molecular mechanisms controlling TEC development, function, dysfunction, and regeneration.
Assuntos
Células Epiteliais/metabolismo , Linfócitos T/fisiologia , Timo/patologia , Animais , Autoimunidade , Diferenciação Celular , Células Epiteliais/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica , Timo/imunologia , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper> T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities.
Assuntos
Colite/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Síndrome de Emaciação/imunologia , Animais , Autoantígenos/imunologia , Autoimunidade , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/transplanteRESUMO
Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.
Assuntos
Diabetes Gestacional/imunologia , Morte Fetal/etiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Linfócitos T Reguladores/imunologia , Timo/imunologia , Adipócitos/patologia , Animais , Proliferação de Células , Diabetes Gestacional/etiologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Células Epiteliais/imunologia , Feminino , Feto/imunologia , Feto/metabolismo , Feto/patologia , Glucose/metabolismo , Intolerância à Glucose/genética , Humanos , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Placenta/imunologia , Placenta/patologia , Gravidez , Receptor Ativador de Fator Nuclear kappa-B/deficiência , Receptor Ativador de Fator Nuclear kappa-B/genética , Linfócitos T Reguladores/citologia , Timo/citologia , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
The thymus is a unique primary lymphoid organ that supports the production of self-tolerant T-cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus-dependent T-cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T-cell clones, thereby counterbalancing the potential for random T-cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self-tolerant T-cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.
Assuntos
Linfócitos T , Timo , Timo/metabolismo , Diferenciação Celular , Células Epiteliais/metabolismoRESUMO
γδT cells are produced in the thymus throughout life and provide immunity at epithelial-rich sites. Unlike conventional αßT cells, γδT-cell development involves intrathymic acquisition of effector function, with priming for either IL17 or IFN-γ production occurring during embryonic or adult life, respectively. How the thymus controls effector-primed γδT-cell generation in adulthood is poorly understood. Here, we distinguished de novo γδT cells from those undergoing thymus recirculation and/or retention using Rag2GFP mice alongside markers of maturation/effector priming including CD24, CD25, CD73, and IFN-γ, the latter by crossing with IFN-γYFP GREAT mice. We categorize newly developing γδT-cells into an ordered sequence where CD25+ CD73- IFN-γYFP- precursors are followed sequentially by CD25- CD73+ IFN-γYFP- intermediates and CD25- CD73+ IFN-γYFP+ effectors. To determine intrathymic requirements controlling this sequence, we examined γδT-cell development in Relb-/- thymus grafts that lack medullary microenvironments. Interestingly, medulla deficiency did not alter CD25+ γδT-cell precursor generation, but significantly impaired development of effector primed stages. This impact on γδT-cell priming was mirrored in plt/plt mice lacking the medullary chemoattractants CCL19 and CCL21, and also Ccl21a-/- but not Ccl19-/- mice. Collectively, we identify the medulla as an important site for effector priming during adult γδT-cell development and demonstrate a specific role for the medullary epithelial product CCL21 in this process.
Assuntos
Interferon gama , Timo , Animais , Camundongos , Diferenciação Celular , Receptores de Antígenos de Linfócitos T gama-delta/genéticaRESUMO
Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing "signature" (c-Met(+)CCR4(+)CXCR3(+)). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Coração/fisiologia , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Linfócitos T/fisiologia , Animais , Comunicação Autócrina , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Células Cultivadas , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Humanos , Memória Imunológica , Indóis/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , RNA Interferente Pequeno/genética , Receptores CCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sulfonas/farmacologia , Linfócitos T/efeitos dos fármacosRESUMO
In the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells support αßT cell development from lymphoid progenitors. For cTECs, expression of a specialized gene signature that includes Cxcl12, Dll4, and Psmb11 enables the cortex to support T lineage commitment and the generation and selection of CD4+CD8+ thymocytes. Although the importance of cTECs in T cell development is well defined, mechanisms that shape the cTEC compartment and regulate its functional specialization are unclear. Using a Cxcl12 DsRed reporter mouse model, we show that changes in Cxcl12 expression reveal a developmentally regulated program of cTEC heterogeneity. Although cTECs are uniformly Cxcl12 DsRed+ during neonatal stages, progression through postnatal life triggers the appearance of Cxcl12 DsRed- cTECs that continue to reside in the cortex alongside their Cxcl12 DsRed+ counterparts. This appearance of Cxcl12 DsRed- cTECs is controlled by maturation of CD4-CD8-, but not CD4+CD8+, thymocytes, demonstrating that stage-specific thymocyte cross-talk controls cTEC heterogeneity. Importantly, although fate-mapping experiments show both Cxcl12 DsRed+ and Cxcl12 DsRed- cTECs share a common Foxn1 + cell origin, RNA sequencing analysis shows Cxcl12 DsRed- cTECs no longer express Foxn1, which results in loss of the FOXN1-dependent cTEC gene signature and may explain the reduced capacity of Cxcl12 DsRed- cTECs for thymocyte interactions. In summary, our study shows that shaping of the cTEC compartment during the life course occurs via stage-specific thymocyte cross-talk, which drives loss of Foxn1 expression and its key target genes, which may then determine the functional competence of the thymic cortex.
RESUMO
In the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells support αßT cell development from lymphoid progenitors. For cTECs, expression of a specialized gene signature that includes Cxcl12, Dll4, and Psmb11 enables the cortex to support T lineage commitment and the generation and selection of CD4+CD8+ thymocytes. Although the importance of cTECs in T cell development is well defined, mechanisms that shape the cTEC compartment and regulate its functional specialization are unclear. Using a Cxcl12DsRed reporter mouse model, we show that changes in Cxcl12 expression reveal a developmentally regulated program of cTEC heterogeneity. Although cTECs are uniformly Cxcl12DsRed+ during neonatal stages, progression through postnatal life triggers the appearance of Cxcl12DsRed- cTECs that continue to reside in the cortex alongside their Cxcl12DsRed+ counterparts. This appearance of Cxcl12DsRed- cTECs is controlled by maturation of CD4-CD8-, but not CD4+CD8+, thymocytes, demonstrating that stage-specific thymocyte cross-talk controls cTEC heterogeneity. Importantly, although fate-mapping experiments show both Cxcl12DsRed+ and Cxcl12DsRed- cTECs share a common Foxn1+ cell origin, RNA sequencing analysis shows Cxcl12DsRed- cTECs no longer express Foxn1, which results in loss of the FOXN1-dependent cTEC gene signature and may explain the reduced capacity of Cxcl12DsRed- cTECs for thymocyte interactions. In summary, our study shows that shaping of the cTEC compartment during the life course occurs via stage-specific thymocyte cross-talk, which drives loss of Foxn1 expression and its key target genes, which may then determine the functional competence of the thymic cortex.
RESUMO
Lymphocytes normally develop within anatomically distinct tissues. In Cell Reports, Swann et al. (2014) reconstruct the primordial thymus and suggest that it was a site of combined T and B lymphopoiesis before evolving into an organ specialized for T cell production.
Assuntos
Proteínas do Olho/genética , Fatores de Transcrição Forkhead/genética , Timo/metabolismo , AnimaisRESUMO
Acquisition of planar cell polarity (PCP) in epithelia involves intercellular communication, during which cells align their polarity with that of their neighbors. The transmembrane proteins Frizzled (Fz) and Van Gogh (Vang) are essential components of the intercellular communication mechanism, as loss of either strongly perturbs the polarity of neighboring cells. How Fz and Vang communicate polarity information between neighboring cells is poorly understood. The atypical cadherin, Flamingo (Fmi), is implicated in this process, yet whether Fmi acts permissively as a scaffold or instructively as a signal is unclear. Here, we provide evidence that Fmi functions instructively to mediate Fz-Vang intercellular signal relay, recruiting Fz and Vang to opposite sides of cell boundaries. We propose that two functional forms of Fmi, one of which is induced by and physically interacts with Fz, bind each other to create cadherin homodimers that signal bidirectionally and asymmetrically, instructing unequal responses in adjacent cell membranes to establish molecular asymmetry.
Assuntos
Caderinas/metabolismo , Polaridade Celular , Proteínas de Drosophila/metabolismo , Drosophila/citologia , Drosophila/metabolismo , Transdução de Sinais , Animais , Receptores Frizzled/metabolismo , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mapeamento de Interação de Proteínas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+ mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi (MHCIIhi CD80hi ) compartment into mTECA/hi (CD24- Sca1- ), mTECB/hi (CD24+ Sca1- ), and mTECC/hi (CD24+ Sca1+ ). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire- cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi , mTECB/hi , and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.
Assuntos
Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Queratinócitos/imunologia , Timo/imunologia , Fatores de Transcrição/genética , Animais , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/imunologia , Proteína AIREAssuntos
Autoantígenos/genética , Células Epiteliais/imunologia , RNA Mensageiro/metabolismo , Tolerância a Antígenos Próprios/imunologia , Linfócitos T/imunologia , Timo/imunologia , Autoantígenos/imunologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Timo/citologiaRESUMO
In the thymus, distinct cortex and medulla areas emphasize the division of labor in selection events shaping the αßT cell receptor repertoire. For example, MHC restriction via positive selection is a unique property of epithelial cells in the thymic cortex. Far less clear are the events controlling tolerance induction in the medulla. By acting in concert through multiple roles, including antigen production/presentation and chemokine-mediated control of migration, we propose that medullary epithelium and dendritic cells collectively enable the medulla to balance T cell production with negative selection and Foxp3+ regulatory T cell (Treg) development. We examine here the features of these medullary resident cells and their roles in T cell tolerance, and discuss how imbalance in the thymus can result in loss of T cell tolerance.
Assuntos
Tolerância Imunológica/imunologia , Timo/imunologia , Animais , Células Dendríticas/imunologia , Células Epiteliais/imunologia , Camundongos , Linfócitos T/imunologiaRESUMO
Lymph node development during embryogenesis involves lymphotoxin-ß receptor engagement and subsequent differentiation of a poorly defined population of mesenchymal cells into lymphoid tissue organizer cells. Here, we showed that embryonic mesenchymal cells with characteristics of adipocyte precursors present in the microenvironment of lymph nodes gave rise to lymph node organizer cells. Signaling through the lymphotoxin-ß receptor controlled the fate of adipocyte precursor cells by blocking adipogenesis and instead promoting lymphoid tissue stromal cell differentiation. This effect involved activation of the NF-κB2-RelB signaling pathway and inhibition of the expression of the key adipogenic factors Pparγ and Cebpα. In vivo organogenesis assays show that embryonic and adult adipocyte precursor cells can migrate into newborn lymph nodes and differentiate into a variety of lymph node stromal cells. Thus, we propose that adipose tissues act as a source of lymphoid stroma for lymph nodes and other lymphoid structures associated with fat.
Assuntos
Adipócitos/imunologia , Linfonodos/imunologia , Transdução de Sinais , Adipócitos/citologia , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Receptor beta de Linfotoxina/imunologia , Camundongos , Subunidade p52 de NF-kappa B/imunologia , Subunidade p52 de NF-kappa B/metabolismo , Fenótipo , Células Estromais/imunologia , Fator de Transcrição RelB/imunologia , Fator de Transcrição RelB/metabolismoRESUMO
The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αß T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αß T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.
Assuntos
Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/imunologia , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Fatores de Transcrição/imunologia , Animais , Diferenciação Celular/imunologia , Microambiente Celular , Células Epiteliais/imunologia , Feminino , Feto/citologia , Feto/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Transdução de Sinais/imunologia , Timo/citologia , Timo/imunologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Proteína AIRERESUMO
The BM serves as a blood-forming organ, but also supports the maintenance and immune surveillance function of many T cells. Yet, in contrast to other organs, little is known about the molecular mechanisms that drive T-cell migration to and localization inside the BM. As BM accumulates many CXCR3-expressing memory CD8+ T cells, we tested the involvement of this chemokine receptor, but found that CXCR3 is not required for BM entry. In contrast, we could demonstrate that CXCR4, which is highly expressed on both naive and memory CD8+ T cells in BM, is critically important for homing of all CD8+ T-cell subsets to the BM in mice. Upon entry into the BM parenchyma, both naïve and memory CD8+ T cells locate close to sinusoidal vessels. Intravital imaging experiments revealed that CD8 T cells are surprisingly immobile and we found that they interact with ICAM-1+VCAM-1+BP-1+ perivascular stromal cells. These cells are the major source of CXCL12, but also express key survival factors and maintenance cytokines IL-7 and IL-15. We therefore conclude that CXCR4 is not only crucial for entry of CD8+ T cells into the BM, but also controls their subsequent localization toward BM niches that support their survival.
Assuntos
Medula Óssea/imunologia , Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular/imunologia , Microambiente Celular , Receptores CXCR4/metabolismo , Animais , Medula Óssea/irrigação sanguínea , Medula Óssea/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular/imunologia , Microambiente Celular/genética , Microambiente Celular/imunologia , Citocinas/biossíntese , Memória Imunológica , Camundongos , Receptores CXCR3 , Células Estromais/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
Assuntos
Alergia e Imunologia/normas , Separação Celular/métodos , Separação Celular/normas , Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Consenso , Humanos , FenótipoRESUMO
Most αß T cells that form in the thymus are generated during mainstream conventional thymocyte development and involve the generation and selection of a diverse αß TCR repertoire that recognizes self-peptide/MHC complexes. Additionally, the thymus also supports the production of T cell subsets that express αß TCRs but display unique developmental and functional features distinct from conventional αß T cells. These include multiple lineages of CD1d-restricted invariant NKT (iNKT) cells that express an invariant αß TCR, branch off from mainstream thymocytes at the CD4+CD8+ stage, and are potent producers of polarizing cytokines. Importantly, and despite their differences, iNKT cells and conventional αß T cells share common requirements for thymic epithelial microenvironments during their development. Moreover, emerging evidence suggests that constitutive cytokine production by iNKT cells influences both conventional thymocyte development and the intrathymic formation of additional innate CD8+ αß T cells with memory-like properties. In this article, we review evidence for an intrathymic innate lymphocyte network in which iNKT cells play key roles in multiple aspects of thymus function.
RESUMO
During αß T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αß TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα- conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11c+MHC class II-Sirpα-Flt3+ cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in Ccr7-/- mice. Moreover, thymic cDC1 defects in Ccr7-/- mice are mirrored in plt/plt mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser (Ccl21a-/- ) or CCL19 (Ccl19-/-) demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool.
Assuntos
Quimiocina CCL21/metabolismo , Células Dendríticas/metabolismo , Receptores CCR7/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Animais , Movimento Celular/fisiologia , Tolerância Imunológica/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80loMHC class IIlo medullary TEC displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development, and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of stem cell Ag-1hi cTEC, and, in early life, a decrease in medullary TEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4 single-positive and CD8 single-positive numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.