Chapter 7 Lymphocyte Receptor Signaling

• Antigen receptors


  Consist of variable antigen-binding chains associated with invariant chains that carry out the signaling function of the receptor

  
• CD3


  • Composed of 3 proteins: γ (gamma), δ (delta), ε (epsilon)

  
• Immuno-receptor tyrosine-based activation motif (ITAM)


  Signaling function of the receptor

  
• Zeta chain


  Only found in T cells, functions in: 1. Signal transduction, 2. Chaperone (escort) the α and β chain to the cell surface

  
• Antigen recognition by the T-cell receptor and its co-receptors

  1. Leads to phosphorylation of ITAMs by Src family kinases

  2. Generates the first intracellular signal in a signaling cascade

  
• Phosphorylated ITAMs


  Provide binding sites for SH2 proteins

  
• Phosphorylated ITAMs


  Recruit and activate the tyrosine kinase ZAP-70

  
• Lck


  Kinase that is constitutively associated with CD4 and CD8 and will phosphorylate the ITAMs

  
• ZAP-70


  Binds to phosphorylated ITAMs

  
• Activated ZAP-70


  Phosphorylates adaptor proteins and promotes PI 3-kinase activation

  
• ZAP-70


  Phosphorylates LAT and SLP-76, initiating four downstream signaling modules

  
• Activated PLC-γ


  Generates the second messengers diacylglycerol (DAG)and inositol trisphosphate (IP3) that lead to transcription factor activation

  
• Phosphorylated LAT and SLP-76


  Linked by the adaptor protein Gads

  
• Phospholipase C-γ


  Brought to membrane and binds to PIP3

  
• Itk


  Cytoplasmic kinase that phosphorylates PLC-γ after it binds to LAT/SLP-76

  
• Activated PLC-γ


  Generates 2 important signaling molecules: 1. Ca2+ entry, 2. Activation of Ras, 3. Activation of protein kinase C-θ

  
• STIM1


  Clusters in ER membrane when Ca2+ leaves the ER, causing opening of calcium release-activated calcium channels (CRAC)

  
• PKC-θ and Ras-GRP


  Recruited by diacylglycerol

  
• Activation of PLC-γ


  Splits the antigen-signaling pathway into 3 branches that will each activate a different transcription factor

  
• Ca2+ entry


  Activates the transcription factor NFAT

  
• Ras activation


  Stimulates the mitogen-activated protein kinase (MAPK) relay and induces expression of the transcription factor AP-1

  Ras has GDP attached (inactive)

  RAS-GRP binds to DAG for exchange of GTP for GDP

  SDS is a protein that helps RAS

  
• RasGRP


  Guanine-nucleotide exchange factor
• AP-1


  Transcription factor formed as a result of the Ras/MAPK pathway, composed of c-Fos and c-Jun

  
• Protein kinase C


  Activates the transcription factors NFκB and AP-1

  
• Igα and Igβ


  Required for receptor transport to surface and signal transduction

  
• The logic of B-cell receptor signaling is similar to that of T-cell receptor signaling, but some of the signaling components are specific to B cells

  
• Receptor-associated kinases (Blk, Fyn, Lyn)


  Phosphorylate the ITAMs

  
• Syk


  Tyrosine kinase that will bind to the phosphorylated ITAMs

  
• B cell co-receptor


  Complex of proteins, unlike T cells
• C3dg


  Breakdown product of C3
• CD28


  Cell-surface protein, a required co-stimulatory signaling receptor for naive T-cell activation

  
• Naïve T cells require an additional signal for activation - Co-stimulatory signal CD28

  
• Maximal activation of PLC-γ, which is important for transcription factor activation, requires a co-stimulatory signal induced by CD28

  
• CD4 are responsible for adhesion and cell transduction
• Important step in T Cell Activation 


  PLC-y is activated by ItK and cleaves PIP2 to yield DAG and IP3
• After important step of T cell activation it activates 3 transcription factors


  NFAT, NFkB, and Fos
• 3 Kinases used in MAPK pathway

  Raf, MEk, Erk
• Ras activates RAf then activates Mek then activates Erk
• Erk interacts with transcription in nucleus, phosphorylates and sets

  transcription factor
• If there is no CD3, there is no expression of 


  T cell receptor