RESUMO
Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin ß7 (Itgb7, Ly69) by binding to the ß7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the ß7 promoter, indicating that these factors may compete for target sequence(s). Whereas ß7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because ß7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when ß7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer's patches, much like ß7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of ß7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of ß7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.
Assuntos
Linfócitos B/imunologia , Cadeias beta de Integrinas/genética , Fatores de Transcrição Kruppel-Like/genética , Linfopoese/imunologia , Animais , Antígenos CD11/biossíntese , Diferenciação Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA , Regulação da Expressão Gênica/imunologia , Cadeias alfa de Integrinas/biossíntese , Fatores de Transcrição Kruppel-Like/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nódulos Linfáticos Agregados/imunologia , Regiões Promotoras Genéticas , Ligação Proteica , Fator de Resposta Sérica/genéticaRESUMO
CD8(+) T cells undergo rapid expansion during infection with intracellular pathogens, which is followed by swift and massive culling of primed CD8(+) T cells. The mechanisms that govern the massive contraction and maintenance of primed CD8(+) T cells are not clear. We show in this study that the transcription factor, FoxO3a, does not influence Ag presentation and the consequent expansion of CD8(+) T cell response during Listeria monocytogenes infection, but plays a key role in the maintenance of memory CD8(+) T cells. The effector function of primed CD8(+) T cells as revealed by cytokine secretion and CD107a degranulation was not influenced by inactivation of FoxO3a. Interestingly, FoxO3a-deficient CD8(+) T cells displayed reduced expression of proapoptotic molecules BIM and PUMA during the various phases of response, and underwent reduced apoptosis in comparison with wild-type cells. A higher number of memory precursor effector cells and memory subsets was detectable in FoxO3a-deficient mice compared with wild-type mice. Furthermore, FoxO3a-deficient memory CD8(+) T cells upon transfer into normal or RAG1-deficient mice displayed enhanced survival. These results suggest that FoxO3a acts in a cell-intrinsic manner to regulate the survival of primed CD8(+) T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Forkhead/imunologia , Memória Imunológica/imunologia , Listeriose/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Animais , Apresentação de Antígeno , Antígenos de Bactérias/imunologia , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Linfócitos T CD8-Positivos/metabolismo , Citocinas/sangue , Citotoxicidade Imunológica , Feminino , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/deficiência , Proteínas de Homeodomínio/genética , Selectina L/biossíntese , Selectina L/genética , Listeria monocytogenes/imunologia , Listeriose/sangue , Subpopulações de Linfócitos/metabolismo , Linfocinas/metabolismo , Proteínas de Membrana Lisossomal/imunologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/genética , Ovalbumina/imunologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Receptores de Interleucina-7/biossíntese , Receptores de Interleucina-7/genética , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genéticaRESUMO
Naive T cells recirculate between the spleen and lymph nodes where they mount immune responses when meeting dendritic cells presenting foreign antigen. As this may happen anywhere, naive T cells ought to visit all lymph nodes. Here, deep sequencing almost-complete TCR repertoires led to a comparison of different lymph nodes within and between individual mice. We find strong evidence for a deterministic CD4/CD8 lineage choice and a consistent spatial structure. Specifically, some T cells show a preference for one or multiple lymph nodes, suggesting that their TCR interacts with locally presented (self-)peptides. These findings are mirrored in TCR-transgenic mice showing localized CD69 expression, retention, and cell division. Thus, naive T cells intermittently sense antigenically dissimilar niches, which is expected to affect their homeostatic competition.
Assuntos
Linfonodos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T , Animais , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígenos CD/metabolismo , Antígenos CD/genética , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.
Assuntos
Diferenciação Celular/genética , Fatores de Transcrição Kruppel-Like/fisiologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/fisiologia , Linfopoese/genética , Mucosa/imunologia , Animais , Antígenos CD19/genética , Antígenos CD19/metabolismo , Células Cultivadas , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Mucosa/metabolismo , Mucosa/fisiologiaRESUMO
Krüppel-like factor 3 (Klf3) is a member of the Klf family of transcription factors. Klfs are widely expressed and have diverse roles in development and differentiation. In this study, we examine the function of Klf3 in B cell development by studying B lymphopoiesis in a Klf3 knockout mouse model. We show that B cell differentiation is significantly impaired in the bone marrow, spleen, and peritoneal cavity of Klf3 null mice and confirm that the defects are cell autonomous. In the bone marrow, there is a reduction in immature B cells, whereas recirculating mature cells are noticeably increased. Immunohistology of the spleen reveals a poorly structured marginal zone (MZ) that may in part be caused by deregulation of adhesion molecules on MZ B cells. In the peritoneal cavity, there are significant defects in B1 B cell development. We also report that the loss of Klf3 in MZ B cells is associated with reduced BCR signaling strength and an impaired ability to respond to LPS stimulation. Finally, we show increased expression of a number of Klf genes in Klf3 null B cells, suggesting that a Klf regulatory network may exist in B cells.
Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Linfopoese/genética , Linfopoese/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritônio/imunologia , Peritônio/metabolismo , Peritônio/patologia , Quimera por Radiação/genética , Quimera por Radiação/imunologia , Baço/imunologia , Baço/metabolismo , Baço/patologiaRESUMO
The thymus continuously produces T lymphocytes that contribute to the maintenance of the peripheral T cell pool. Since peripheral recirculating T cells represent a very minor population among total thymocytes in normal animals, the relationship between the thymus and secondary lymphoid organs is generally considered unidirectional. Recently, several reports have described the presence of recirculating T cells in the thymus, raising issues regarding their possible function. In this article, we show that the niche for recirculating T cells in the thymus, i.e., their absolute number, is the same in lymphopenic and normal mice. Using a novel combination of TCR-transgenic mice in which the ligand necessary for positive selection of host T cells is only expressed by transferred donor T cells, we show that mature T cells recirculating back to the thymus can mediate positive selection.
Assuntos
Linfócitos T/imunologia , Timo/imunologia , Animais , Diferenciação Celular , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Parabiose , Linfócitos T/metabolismo , Timo/fisiologiaRESUMO
Institutionalization is generally a consequence of functional decline driven by physical limitations, cognitive impairments, and/or loss of social supports. At this stage, intervention to reverse functional losses is often too late. To be more effective, geriatric medicine must evolve to intervene at an earlier stage of the disability process. Could nursing homes (NHs) transform from settings in which many residents dwell to settings in which the NH residents and those living in neighboring communities benefit from staff expertise to enhance quality of life and maintain or slow functional decline? A task force of clinical researchers met in Toulouse on December 2, 2015, to address some of these challenges: how to prevent or slow functional decline and disabilities for NH residents and how NHs may promote the prevention of functional decline in community-dwelling frail elderly. The present article reports the main results of the Task Force discussions to generate a new paradigm.
Assuntos
Disfunção Cognitiva/prevenção & controle , Idoso Fragilizado , Casas de Saúde , Atividades Cotidianas , Idoso , Humanos , Estados UnidosRESUMO
The sizes of lymphocyte populations in lymphoid organs of nicotinic acetylcholine receptor knockout and chimera (knockout/wild-type) mice were studied by flow cytometry. The absence of beta2 subunit decreased, while nicotine treatment increased B lymphocyte numbers in the bone marrow. In chimera mice, either beta2 or alpha7 subunits influenced lymphocyte populations in primary lymphoid organs, while in the spleen, only alpha7 receptors were critical. More annexin V-positive B cells were found in the bone marrow of knockout than wild-type animals. We conclude that nicotinic receptors are involved in regulating lymphocyte development and control the B lymphocyte survival.
Assuntos
Processos de Crescimento Celular/fisiologia , Linfócitos/fisiologia , Receptores Nicotínicos/fisiologia , Animais , Antígenos CD/metabolismo , Comportamento Animal , Transplante de Medula Óssea/métodos , Contagem de Células/métodos , Citometria de Fluxo/métodos , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Linfócitos/classificação , Masculino , Camundongos , Camundongos Knockout , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Quimera por Radiação/fisiologia , Receptores Nicotínicos/deficiência , Baço/metabolismo , Baço/efeitos da radiação , Fator Tímico Circulante/metabolismo , Fator Tímico Circulante/efeitos da radiação , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Regulator of G-protein signaling (RGS) proteins negatively regulate signaling pathways involving seven transmembrane receptors and heterotrimeric G proteins. The purpose of this study was to determine the chromosomal localization, structure and expression profile of the gene coding for mouse regulator of G-protein signaling10 (mRGS10). Fluorescence in situ hybridization analysis indicated that mRGS10 maps to band F3-F4 of the mouse chromosome 7. Sequence analysis revealed that the RGS10 gene encompasses six exons spanning more than 40 kb of genomic DNA. The RGS domain is encoded by exons 3-6; alternative splicing of the first exons allows the generation of two isoforms in the mouse system which differ in their N-terminal portion. Thus, mRGS10 encodes two intracellular proteins of 167 and 181 amino-acids which are highly homologous to the human and rat polypeptides. The deduced amino-acid sequences of mouse RGS10 show 92% sequence identity to their orthologues from human. The mRGS10 gene is expressed predominantly in brain and testis but it is also found in heart, lung, bone marrow, lymph node and spleen. Differential display between mature B lymphocytes and marginal zone B cells, as well as reverse transcription-polymerase chain reaction and Northern blot, showed that mRGS10 is differentially transcribed during B-cell differentiation. Finally, mRGS10 protein was detected in plasma cells of secondary lymphoid organs by immunofluorescence.
Assuntos
Genes/genética , Proteínas RGS/genética , Sequência de Aminoácidos , Animais , Linfócitos B/metabolismo , Northern Blotting , Linhagem Celular , Mapeamento Cromossômico , Éxons , Feminino , Expressão Gênica , Hibridização in Situ Fluorescente , Íntrons , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência de Aminoácidos , Células Tumorais CultivadasRESUMO
In young adult mice, the thymus produces about a million newly formed T cells every day that colonize peripheral lymphoid tissues. Mostly regarded as a primary lymphoid organ only, the relationship between the thymus and peripheral lymphoid organs is considered unidirectional. However, this perception has been challenged by reports showing that peripheral lymphocytes, mostly T cells, can migrate back into the thymus. The presence of recirculating T cells in the thymus is rather incongruous and raises the question: is the presence of 'peripheral' T cells in the thymus superfluous or do these cells fulfill some relevant physiologic functions? There is now evidence that cells of the hematopoietic lineage, including T cells, can play an active role during thymocyte selection, a role generally considered the exclusive property of thymic epithelial cells and dendritic cells. Although, on a per cell basis, peripheral T cells in the thymus may be less efficient than thymus epithelial cells or dendritic cells at thymocyte positive and negative selection, they may nevertheless contribute to selection by influencing the selectable TCR repertoire and post-selection T cell functionality. Here, peripheral lymphocytes re-entering the thymus may be envisioned as Trojan horses as these cells may introduce antigens necessary for both positive and negative selection of T cells.
Assuntos
Movimento Celular/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Deleção Clonal , Humanos , CamundongosRESUMO
T cell survival and homeostatic proliferation in the periphery requires T cell receptor (TCR) binding to restricting major histocompatability complex (MHC)-encoded molecules, as well as the availability of certain lymphokines. However, the exact mechanisms by which these signals interrelate and contribute to homeostasis are not understood. By performing T cell transfers into TCR transgenic hosts we detected a hierarchical order of homeostatic proliferation for T cells differing in MHC restriction, such that OT1 cells (K(b) restricted) proliferated in P14 (D(b)-restricted TCR) recipients, but not vice versa. Using K(b) mutant mice, we demonstrated that proliferation of OT1 cells in P14 recipients, as well as the ability of host OT1 cells to hinder the proliferation of donor P14 cells, were dependent on OT1-TCR binding to K(b) molecules. However, interclonal T cell competition was not mediated simply by competition for physical access to the MHC-bearing cell. This was shown in parabiotic pairs of OT1 and K(b) mutant mice in which P14 cells failed to proliferate, even though the OT1 cells could not interact with half of the APCs in the system. Thus, we conclude that the interaction between the TCR and restricting MHC molecule influences the ability to compete for trophic resources not bound to the stimulating APC. This mechanism allows a local competitiveness that extends beyond a T cell's specificity.
Assuntos
Proliferação de Células , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Homeostase , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/fisiologiaRESUMO
During the postnatal development, astrocytic cells in the neocortex progressively lose their neural stem cell (NSC) potential, whereas this peculiar attribute is preserved in the adult subventricular zone (SVZ). To understand this fundamental difference, many reports suggest that adult subventricular GFAP-expressing cells might be maintained in immature developmental stage. Here, we show that S100B, a marker of glial cells, is absent from GFAP-expressing cells of the SVZ and that its onset of expression characterizes a terminal maturation stage of cortical astrocytic cells. Nevertheless, when cultured in vitro, SVZ astrocytic cells developed as S100B expressing cells, as do cortical astrocytic cells, suggesting that SVZ microenvironment represses S100B expression. Using transgenic s100b-EGFP cells, we then demonstrated that S100B expression coincides with the loss of neurosphere forming abilities of GFAP expressing cells. By doing grafting experiments with cells derived from beta-actin-GFP mice, we next found that S100B expression in astrocytic cells is repressed in the SVZ, but not in the striatal parenchyma. Furthermore, we showed that treatment with epidermal growth factor represses S100B expression in GFAP-expressing cells in vitro as well as in vivo. Altogether, our results indicate that the S100B expression defines a late developmental stage after which GFAP-expressing cells lose their NSC potential and suggest that S100B expression is repressed by adult SVZ microenvironment.
Assuntos
Encéfalo/crescimento & desenvolvimento , Proteína Glial Fibrilar Ácida/metabolismo , Fatores de Crescimento Neural/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Proteínas S100/metabolismo , Células-Tronco/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/citologia , Astrócitos/metabolismo , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/fisiologia , Células Cultivadas , Corpo Estriado/citologia , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neurônios/citologia , Subunidade beta da Proteína Ligante de Cálcio S100 , Esferoides Celulares , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacosRESUMO
In pre-Talpha (pTalpha) gene-deleted mice, the positively selectable CD4+ CD8+ double-positive thymocyte pool is only 1% that in wild-type mice. Consequently, their peripheral T cell compartment is severely lymphopenic with a concomitant increase in proportion of CD25+ FoxP3+ regulatory T cells. Using mixed bone marrow chimeras, where thymic output was 1% normal, the pTalpha(-/-) peripheral T cell phenotype could be reproduced with normal cells. In the pTalpha(-/-) thymus and peripheral lymphoid organs, FoxP3+ CD4+ cells were enriched. Parabiosis experiments showed that many pTalpha(-/-) CD4+ single-positive thymocytes represented recirculating peripheral T cells. Therefore, the enrichment of FoxP3+ CD4+ single-positive thymocytes was not solely due to increased thymic production. Thus, the pTalpha(-/-) mouse serves as a model system with which to study the consequences of chronic decreased thymic T cell production on the physiology of the peripheral T cell compartment.
Assuntos
Linfopenia/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Linfócitos T/citologia , Animais , Transplante de Medula Óssea , Camundongos , Camundongos Knockout , Parabiose , Timo/citologia , Quimeras de TransplanteRESUMO
IL-7 is critically involved in regulating peripheral T cell homeostasis. To investigate the role of IL-7 on lymphopenia-induced proliferation of polyclonal lymphocytes, we have transferred CFSE-labeled cells into a novel T-lymphopenic, IL-7-transgenic mouse line. Results obtained indicate that T and B cells do not respond in the same way to IL-7-homeostatic signals. Overexpression of IL-7 enhances proliferation of both CD4(+) and CD8(+) T cells but with distinctly temporal effects. Expansion of naturally arising CD4(+)-regulatory T cells was like that of conventional CD4(+) T cells. IL-7 had no effect on B cell proliferation. By immunohistology, transferred T cells homed to T cell areas of spleen lymphoid follicles. Increasing IL-7 availability enhanced T cell recovery by promoting cell proliferation and reducing apoptosis during early stages of lymphopenia-induced proliferation. Taken together, these results provide new insights into the pleiotropic effects of IL-7 on lymphopenia-induced T cell proliferation.
Assuntos
Interleucina-7/metabolismo , Linfócitos/imunologia , Linfócitos/patologia , Linfopenia/imunologia , Linfopenia/patologia , Transferência Adotiva , Animais , Apoptose , Linfócitos B/imunologia , Linfócitos B/patologia , Complexo CD3/genética , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Feminino , Expressão Gênica , Homeostase , Interleucina-7/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
The immune response of T lymphocytes to pathogens is initiated in draining secondary lymphoid organs, and activated cells then migrate to the site of infection. Thus, control of naive and regulatory CD4+ T-cell migration is crucial; however, it is poorly understood in physiological and pathological conditions. We found that CD4+ subpopulations displayed characteristic regulator of G-protein signalling (RGS) gene expression profiles. Regulatory T cells express higher levels of RGS1, RGS9 and RGS16 than naive cells. These genes are up-regulated upon cell activation and their level of expression correlates with in vivo cell migration. Using parabiosis, we showed that regulatory T lymphocytes migrate less than naive T cells and that migrant naive T cells express even lower RGS levels than their static counterparts. Our results show an inverse correlation between the capacity to migrate and the levels of RGS1, RGS9 and RGS16 for both naive and regulatory T cells. Taken together, these results suggest a role for RGS molecules in chemokine-induced lymphocyte migration and demonstrate the peculiarity of regulatory T cells in terms of phenotype and migration ability, providing new insights into their function.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Proteínas RGS/imunologia , Animais , Feminino , Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parabiose , Reação em Cadeia da Polimerase/métodos , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores de Interleucina-2/análise , Transdução de Sinais/imunologiaRESUMO
I analyzed how B cell survival, the rate of B cell division and the rate of B cell activation may be affected in mice with different numbers of peripheral B cells. For this purpose, I created bone marrow (BM) chimeras with different BM B cell production; I analyzed peripheral B cell dynamics in these animals and studied the fate of carboxyfluorescein succinimidyl ester-labeled lymph node B cells transferred into these mice. I found that in lymphopenic mice, B cell life span is shortened and the rates of terminal B cell differentiation and cell death increased. As a consequence, I did not observe accumulation of B cells in mice with reduced but constant B-cell-poiesis. These results suggest that peripheral B cell survival relies not only on the number of competitors, as previously shown, but also on the rate of throughput of cells in a particular compartment.
Assuntos
Linfócitos B/imunologia , Animais , Linfócitos B/citologia , Diferenciação Celular , Divisão Celular , Sobrevivência Celular , Cinética , Ativação Linfocitária , Contagem de Linfócitos , Linfopenia/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/fisiologia , Quimeras de TransplanteRESUMO
In adult mice, the number of B lymphocytes remains constant under homeostatic control, in spite of the fact that B cells are produced continuously in numbers that largely exceed the number required to replenish the peripheral pools. It follows that each newly formed lymphocyte can only persist if another lymphocyte dies. In an immune system where the total number of cells is limited, cell survival is no longer a passive phenomenon but rather a continuous active process where each lymphocyte must compete with other lymphocytes to survive. Consequently, the number and the life expectancy of a B-cell clone vary according to the presence or absence of competitor populations. This process of lymphocyte competition is likely controlled by a common need for resources that are in limited supply. The number of peripheral B-cells varies according to the availability of B-cell receptor (BCR) ligands. Indeed, it is possible to modify steady-state B-cell numbers by antigen manipulation. Moreover, conventional self-reactive B cells can undergo positive selection. We showed that the fate of a self-reactive B cell is determined by the quantity of self-antigens, the number of antigen-specific receptors engaged, and its overall antigen-binding avidity rather than the affinity of individual BCRs.