RESUMEN
TLR have a crucial role in the detection of microbial infection in mammals. Until recently, most investigations on TLR have focused on cells of the innate immune system and on the role of TLR in the initiation of antigen-specific responses following recognition of microbial products by APC. Here, we report that murine T cells express TLR1, TLR2, TLR6, TLR7 and TLR9 mRNA. Using CD8 T cells from F5 TCR-transgenic mice, we demonstrate that the lipopeptide Pam(3)CysSK(4) (Pam), a synthetic analog of bacterial and mycoplasmal lipoproteins that recognizes TLR1/2 complex, costimulates antigen-activated T cells. Costimulation with Pam permits an increased cell proliferation and survival associated with a sustained CD25 expression and an enhanced expression of Bcl-xL anti-apoptotic protein. In addition, we show that costimulation with Pam up-regulates IFN-gamma production but also granzyme B secretion and cytotoxic activity of antigen-activated T cells, indicating that TLR2 engagement enhances the major effector functions of CD8 T cells. Finally, we demonstrate that TLR2 engagement on T cells lowers the activation threshold for costimulatory signals delivered by APC.
Asunto(s)
Antígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Activación de Linfocitos/inmunología , Receptor Toll-Like 2/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Cultivadas , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , ARN Mensajero/biosíntesis , Receptor Toll-Like 1/metabolismo , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/fisiologíaRESUMEN
We analyzed here the expression of the prosurvival Bcl-2 homologue A1 in peripheral B cell compartment. We observed that A1 mRNA are highly expressed in peripheral B cells as compared with other anti-apoptotic genes of the Bcl-2 family such as bcl-xl and bcl-2 itself. The expression of A1 is up-regulated in immature B cells at the transition between transitional type 1 (T1) and type 2 (T2) cells, and remained highly expressed in mature (M) B cells. We, therefore, analyzed the effect of B cell antigen receptor (BCR) and BAFF receptor (BAFF-R) engagement on the regulation of A1 in total B220(+) cells but also FACS-sorted immature T1, T2 and M B cells. We demonstrated that only BCR engagement up-regulated the expression of A1 mRNA and protein. These results suggest that A1 may play a key role in antigen-dependent signals that are required for survival and/or proliferation of peripheral B cells.
Asunto(s)
Apoptosis , Linfocitos B/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Bazo/citología , Animales , Receptor del Factor Activador de Células B , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/metabolismo , Linfocitos T/metabolismo , Células TH1/metabolismo , Células Th2/metabolismo , Proteína bcl-XRESUMEN
The anti-proliferative effect of Bcl-2 acts mainly at the level of the G0/G1 phase of the cell cycle. Deletions and point mutations in the bcl-2 gene show that the anti-proliferative activity of Bcl-2, can in some cases, be dissociated from its anti-apoptotic function. This indicates that the effect of Bcl-2 on cell cycle progression can be a direct effect and not only a consequence of its anti-apoptotic activity. Bcl-2 appears to mediate its anti-proliferative effect by acting on both signal transduction pathways (NFAT, ERK) and on specific cell cycle regulators (p27, p130).
Asunto(s)
División Celular/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Secuencia de Aminoácidos , Animales , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Humanos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-bcl-2/química , Transducción de SeñalRESUMEN
We have studied the impact of B-cell receptor (BCR) or CD40 ligation on the in vitro chemotactic response of tonsillar B cells to 4 chemokines: stromal cell-derived factor (SDF)-1alpha, macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and B-cell-attracting chemokine (BCA)-1. In the tonsil, SDF-1 and MIP-3alpha are both expressed in the crypt epithelium, while MIP-3beta is found in the T zone and BCA-1 in the follicles. Resting virgin and memory B cells display a similar chemotaxis pattern, and they both have the potential to migrate in vitro to all 4 chemokines studied. This pattern of responsiveness is strongly modified by a surrogate antigen (Ag) but is not altered by CD40 ligand. We report here that surrogate Ag induces a profound and sustained suppression of the response to the crypt chemokines SDF-1alpha and MIP-3alpha, while it exacerbates the migratory response to MIP-3beta. The effect of surrogate Ag on the response to BCA-1 is biphasic: After an initial phase of suppression, chemotaxis toward BCA-1 is strongly up-regulated. Our results suggest that Ag is primarily responsible for reprogramming the B-cell chemotaxis responsiveness during the humoral response. We propose that it initiates an ordered change of the chemotaxis machinery allowing Ag-activated B cells to relocate in the T zone and B-cell follicles sequentially.