RESUMO
Dendritic cells (DCs) have the striking ability to cross-present exogenous antigens in association with major histocompatibility complex (MHC) class I to CD8(+) T cells. However, the intracellular pathways underlying cross-presentation remain ill defined. Current models involve cytosolic proteolysis of antigens by the proteasome and peptide import into endoplasmic reticulum (ER) or phagosomal lumen by the transporters associated with antigen processing (TAP1 and TAP2). Here, we show that DCs expressed an ER-resident 47 kDa immune-related GTPase, Igtp (Irgm3). Igtp resides on ER and lipid body (LB) membranes where it binds the LB coat component ADFP. Inactivation of genes encoding for either Igtp or ADFP led to defects in LB formation in DCs and severely impaired cross-presentation of phagocytosed antigens to CD8(+) T cells but not antigen presentation to CD4(+) T cells. We thus define a new role for LB organelles in regulating cross-presentation of exogenous antigens to CD8(+) T lymphocytes in DCs.
Assuntos
Apresentação de Antígeno/imunologia , Apresentação Cruzada , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Lipídeos/imunologia , Fagocitose , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Retículo Endoplasmático/imunologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/imunologia , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Perilipina-2RESUMO
Immune cells are responsible for pathogen detection and elimination, as well as for signaling to other cells the presence of potential danger. In order to mount an efficient immune response, they need to move and search for a pathogen, interact with other cells, and diversify the population by asymmetric cell division. All these actions are regulated by cell polarity: cell polarity controls cell motility, which is crucial for scanning peripheral tissues to detect pathogens, and recruiting immune cells to sites of infection; immune cells, in particular lymphocytes, communicate with each other by a direct contact called immunological synapse, which entails a global polarization of the cell and plays a role in activating lymphocyte response; finally, immune cells divide asymmetrically from a precursor, generating a diversity of phenotypes and cell types among daughter cells, such as memory and effector cells. This review aims at providing an overview from both biology and physics perspectives of how cell polarity shapes the main immune cell functions.
Assuntos
Divisão Celular Assimétrica , Transdução de Sinais , Linfócitos , Polaridade CelularRESUMO
Diacylglycerol kinases (DGKs) limit antigen receptor signaling in immune cells by consuming the second messenger diacylglycerol (DAG) to generate phosphatidic acid (PA). Here, we showed that DGKζ promotes lymphocyte function-associated antigen 1 (LFA-1)-mediated adhesion and F-actin generation at the immune synapse of B cells with antigen-presenting cells (APCs), mostly in a PA-dependent manner. Measurement of single-cell mechanical force generation indicated that DGKζ-deficient B cells exerted lower forces at the immune synapse than did wild-type B cells. Nonmuscle myosin activation and translocation of the microtubule-organizing center (MTOC) to the immune synapse were also impaired in DGKζ-deficient B cells. These functional defects correlated with the decreased ability of B cells to present antigen and activate T cells in vitro. The in vivo germinal center response of DGKζ-deficient B cells was also reduced compared with that of wild-type B cells, indicating that loss of DGKζ in B cells impaired T cell help. Together, our data suggest that DGKζ shapes B cell responses by regulating actin remodeling, force generation, and antigen uptake-related events at the immune synapse. Hence, an appropriate balance in the amounts of DAG and PA is required for optimal B cell function.