RESUMO
The development and function of B lymphocytes is regulated by numerous signaling pathways, some emanating from the B-cell antigen receptor (BCR). The spleen tyrosine kinase (Syk) plays a central role in the activation of the BCR, but less is known about its contribution to the survival and maintenance of mature B cells. We generated mice with an inducible and B-cell-specific deletion of the Syk gene and found that a considerable fraction of mature Syk-negative B cells can survive in the periphery for an extended time. Syk-negative B cells are defective in BCR, RP105 and CD38 signaling but still respond to an IL-4, anti-CD40, CpG or LPS stimulus. Our in vivo experiments show that Syk-deficient B cells require BAFF receptor and CD19/PI3K signaling for their long-term survival. These studies also shed a new light on the signals regulating the maintenance of the normal mature murine B-cell pool.
Assuntos
Antígenos CD19/imunologia , Linfócitos B/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Tirosina Quinases/imunologia , Transdução de Sinais/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Animais , Anticorpos/farmacologia , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD19/genética , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/imunologia , Linfócitos B/citologia , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/genética , Antígenos CD40/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/genética , Interleucina-4/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Oligodesoxirribonucleotídeos/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Tirosina Quinases/genética , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/genética , Quinase SykRESUMO
Expression of a functional BCR is essential for the development of mature B cells and has been invoked in the control of their maintenance. To test this maintenance function in a new experimental setting, we used the tamoxifen-inducible mb1-CreER(T2) mouse strain to delete or truncate either the mb-1 gene encoding the BCR signaling subunit Igα or the VDJ segment of the IgH (H chain [HC]). In this system, Cre-mediated deletion of the mb-1 gene is accompanied by expression of a GFP reporter. We found that, although the Igα-deficient mature B cells survive for >20 d in vivo, the HC-deficient or Igα tail-truncated B cell population is short-lived, with the HC-deficient cells displaying signs of an unfolded protein response. We also show that Igα-deficient B cells still respond to the prosurvival factor BAFF in culture and require BAFF-R signaling for their in vivo maintenance. These results suggest that, under certain conditions, the loss of the BCR can be tolerated by mature B cells for some time, whereas HC-deficient B cells, potentially generated by aberrant somatic mutations in the germinal center, are rapidly eliminated.
Assuntos
Receptor do Fator Ativador de Células B/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Domínios e Motivos de Interação entre Proteínas/genética , Animais , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/química , Receptor do Fator Ativador de Células B/metabolismo , Sobrevivência Celular/genética , Estresse do Retículo Endoplasmático , Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Deleção de Sequência , Transdução de SinaisRESUMO
Adipose tissue (AT) plays a central role in systemic metabolic homeostasis, but its function during bacterial infection remains unclear. Following subcutaneous bacterial infection, adipocytes surrounding draining lymph nodes initiated a transcriptional response indicative of stimulation with IFN-γ and a shift away from lipid metabolism toward an immunologic function. Natural killer (NK) and invariant NK T (iNKT) cells were identified as sources of infection-induced IFN-γ in perinodal AT (PAT). IFN-γ induced Nos2 expression in adipocytes through a process dependent on nuclear-binding oligomerization domain 1 (NOD1) sensing of live intracellular bacteria. iNOS expression was coupled to metabolic rewiring, inducing increased diversion of extracellular L-arginine through the arginosuccinate shunt and urea cycle to produce nitric oxide (NO), directly mediating bacterial clearance. In vivo, control of infection in adipocytes was dependent on adipocyte-intrinsic sensing of IFN-γ and expression of iNOS. Thus, adipocytes are licensed by innate lymphocytes to acquire anti-bacterial functions during infection.