T Cell Receptor Signaling

T cell antigen receptors (TCR) recognize and bind to MHC associated antigenic peptides that are presented by antigen presenting cells. TCRs have two distinct units: an antigen-recognizing unit comprised of the TCRα -β heterodimer and a signal transduction unit comprised of the CD3 complex. Costimulatory receptors like CD4, CD8 and CD28 contribute to signal transduction by modulating the response threshold.Binding of antigen to TCR initiates a wave of tyrosine kinase activity begining with the Src kinases, LCK and FYN; their activation being enabled by the protein phosphatase CD45. This is followed by the activation of ZAP-70 and subsequently Vav, SLP-6 and LAT proteins. The initial wave of tyrosine phosphorylation leads to the activation of several downstream signaling pathways which include: 1)activation of PLCγ1 leading to increased Ca+2 activation which results in transcriptional activation of IL-2 promoter by NFAT. 2)the Ras/Raf/MEK/ERK activation involves the adapter proteins GRB2 and SOS. ERK activates trascriptional regulators c-Fos and c-Jun. 3)NF-κb activation is mediated by PKCθ activation of IKK 4)Vav activates Rac-1 which then activates the MEKK/MKK/JNK pathway. JNK activates c-Jun.T cells respond to activation by up-regulating various signal transduction pathways which in turn lead to the induction of genes. These genes regulate processes like proliferation,differentiation, apoptosis, anergy, development of memory or cytotoxic killing. The quality of the TCR signal, as well as a host of modifying factors determine the eventual path followed by a T cell. (Upgraded 12/2020)