Pathway: Generation of second messenger molecules
Reactions in pathway: Generation of second messenger molecules :
Generation of second messenger molecules
In addition to serving as a scaffold via auto-phosphorylation, ZAP70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT (step 13) and LCP2. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: PLC-gamma1 (step 14) and GRAP2 (step 15) bind to the LAT on the phosphorylated tyrosine residues. LCP2 is then moved to the signalosome by interacting with the SH3 domains of GRAP2 using their proline rich sequences (step 16). Once LCP2 binds to GRAP2, three LCP2 acidic domain N-term tyrosine residues are phosphorylated by ZAP70 (step 17). These phospho-tyrosine residues act as binding sites to the SH2 domains of ITK (steps 18) and PLC-gamma1 (step 19).
PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by ITK (step 20) and ZAP70 (step 21). Phosphorylated PLC-gamma1 subsequently detaches from LAT and LCP2 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 22). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3 (step 23). These second messengers are involved in PKC and NF-kB activation and calcium mobilization.
Adaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with remarkable diversity tailored to recognize aspects of particular pathogens or antigens. During infection, dendritic cells (DC) which act as sentinels in the peripheral tissues recognize and pick up the pathogen in the form of antigenic determinants and then process these antigens and present them to T cells. These T cells of appropriate specificity respond to the antigen, and either kill the pathogen directly or secrete cytokines that will stimulate B lymphocyte response. B cells provide humoral immunity by secreting antibodies specific for the pathogen or antigen.
Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system.