• antigen receptor heterodimer
• invariant associated proteins that transmit signals

• CD3 complex
• TCR alpha/beta

All associated with motifs called ITAM's

1. ligand binds 
2. phosphorylation of ITAM's by src family kinases
3. phosphorylated ITAM's recruit other Tyr kinases and addaptor proteins
4. this forms macromolecular signaling complex

• BCR
• TCR
• NK cells
• macrophages
• neutrophils
• mast cells
• basophils

allows flexibility of response due to major variations in quantity and quality of second messanger generation

Methods to regulate formation of signaling macromolecular complexes

• protein protein interactions
• cytoskeletal interactions
• segregation into lipid raft membrane microdomains

use SH2, SH3

1. ligand binding clusters receptors, activating Tyr kinases leading to phosphorylation of receptor cytoplasmic domains
2. adaptor proteins bind to phosphotyrosine via their S2 domains
3. other signaling proteins bind to adaptor protein via Proline-rich sequences, becoming concentrated around activated receptor

Mechanism of phopshorylation of scaffolding prtoeins

phosphorylation of scaffolding protein leads to recruit signaling proteins that bind to it

• structure
  • enriched for saturaed lipids and cholesterol
  • can change in size and protein content
  • allow for proteins to migrate into lipid rafts when oligomerized by binding ligands
• contents
  • GPI linked proteins
  • acylated proteins (ex: src family kinases)

How does an immunological synapse form?

• microclusters of TCR complexes form right after MHC-peptide binding
• gradually coalesce into central aggregate
• signal transduction initiated in microclusters within seconds of ligand recognition

CD4

CD8

Co-Receptors for BCR

CD21

CD19

Process of TCR activation in co-receptors

1. binding of ligand to receptor
2. phosphorylation of ITAM by receptor associated kinases
3. ZAP bind to phosphorylated ITAM chaim
4. ZAP is phosphorylated and activated by Lck when co-receptor binds to MHC ligand

1. CD21 binds to CD3 tagged antigens to allow for co-receptor to cluster with antigen receptors
2. co-ligation of coreceptor allows receptor associated kinases of phosphorylated CD19
3. phosphorylated CD19 bind src family and PI-3 kinases
4. PI-3 kinase initiages signaling path to involve GEF protein (vav)

Components of src gene/receptor

SH3 domain

SH2 domain

kinase domain (activating, inhibitory residues)

Enzymes the regulates src family kinases

• Csk phosphorylates inhibitory Tyr
• CD45 dephosphorylates inhibitory Tyr

• recruitment of constitutively active kinases to antigen R by co-receptors
• mobilization of antigen receptor to lipid raft domains after ligand binding promotes access to src family Tyr kinases (SFK's)
• conformational change of antigen receptor complex upon ligand binding exposes ITAM's to SFK's

stimulate phosphatases that will activate Lck and Fyn (receptor associated tyrosine kinases), which contain tyrosine kinase activity that will produce GEF and PLC

1. CD45 phosphatase activate receptor associated tyrosine kinases stimulate
2. Syk (tyrosine kinase) binds to phosphorylated Igβ and become activated
3. activated kinases activate CD19, PLC, GEF's

1. cleave PIP2 into IP3 and DAG
2. DAG and calcium activate PKC, which activates NFkB
3. IP3 incrases intracellular calcium, activating calcineurin (phosphatase)
4. calcineurin activate NFAT (transcription factor)
5. NKkB and NFAT act to induce specific gene transcription, leading to cell proliferation and differentiation

1. GEF's activation of small G proteins
   1. ex: Ras and Rac (bind GTP)
2. small G proteins activate MAP kinase cascade
3. Ras-induced kinase cascade induces and activates Fos (component of AP-1) transcription factor
4. induces specific gene transcription, leading to cell proliferation and differentiation

1. blocks the transcription of calcineurium, which will dephosphorylate NFAT
2. If NFAT still has its phosphates attached, it wont be active

Recruit phosphatases tp membrane associated immunoreceptors that can inhibit tyrosine kinase based activation pathways.

• activate tyrosine phosphatases
• ubiquinylation to degrade signal proteins

• Cbl (ubiquitin ligase)
• if you do not have enough inhibition of cascades, it can cause autoimmune diseases

• co-stimulatory molecules
• cytokine receptors
• pathogen recognition receptors (ex: toll like receptors)

CD28 interacts with B7 to promote:

• cell survival/protect from apoptosis
• IL-2 production leading to proliferation
• cytoskeletal rearrangements, raft recruitment

• activation
• survival
• differentiation

Describe the phenomenon of inside out signalling that occurs in T cells

1. T cell initally binds APC thru low affinity LFA-ICAM interactions
2. subsequent binding of TCR's signals LFA via adhesion and degranulation adaptor protein (ADAP)
3. conformational changes in LFA increase affinity and prolongs cell-cell contact

• It serves as a co-stimulatory signal which is needed for
  • Ig isotype switching
  • germinal center formation
  • memory
  • macrophage activation

ALSO gets help from T cell derived cytokines 

1. cytokine binding dimerize receptor, bringing together cytoplasmic JAK's which activate each other and phosphorylate the receptor
2. TF's (STATS) bind to phosphorylated receptors, and are in turn phosphorylated by activated JAK's
3. phosphorylated STATs form dimers that translocate into nucleus to initate new gene transcription