Chapter 6 Signaling Through Immune System Receptors

1. Chapter 6 Signaling Through Immune System Receptors Ig, TCR, cytokine receptors signal transduction is the change of a signal from one form to another (i.e., passing information along in different forms)

2. Overview • Events controlled by signaling • Development, Activation, Homing, Death • Antigens, cytokines, chemokines, etc. • Antigen receptors: • Associated chains, ITAM’s, tyrosine kinases, adaptors, downstream effectors (more ubiquitous) • Spatial organization: lipid rafts, immunol. synapse (SMAC) • Other receptors: TNFr’s, chemokines, TLR’s

3. Signal Transduction Pathways Relay Information from the Cell Surface to the Nucleus

4. Protein Reversible Protein Phosphorylation is a general mechanism for transmitting signals from the cell membrane P ATP ADP Kinase Protein Phosphatase Pi Major types of phosphorylation: Tyrosine and serine/threonine

5. Specialized domains mediate protein-protein interactions during signal transduction SH2 P Tyr SH3 Poly-proline sequence src-homology 2

6. Two types of receptors that signal through protein kinases Kinaseinactive Kinase active

7. TCR-Responsive Promoters: Models for studying signaling pathways from the TCR to the nucleus Ras/ MAP kinase PKC IKK/IkB Calcium IL-2 CD28- RE AP-1 NFAT NFAT AP-1 NF-B

8. How do TCR and surface Ig access intracellular signaling pathways? • Conserved motif with 2 tyrosines in , CD3 chains and Ig-a and Ig-b proteins • ITAM • Immuno-receptor Tyrosine-based Activation Motif • Also found in receptors on NK and monocytic cells

9. ag The cytoplasmic tail of the BCR does not have catalytic or signaling activity. Instead, BCRs are associated with two invariant chains, Iga and Igb. Aggregation or conformational changes in the Ig molecule causes changes in the Iga and Igb heterodimer that allow it to signal the inside of the cell that antigen has been bound by the surface Ig on the outside of the cell Immunoreceptor tyrosine-based activation motif (ITAM)

10. Similar to BCR, the TCR alone cannot signal the T cell that it has bound antigen The TCR is always associated with CD3 (g,d,e) and z (zeta) chain. These molecules are involved in signaling the T cell when it engages antigen in its TCR The TCR plus CD3 is referred to as the TCR complex

11. CD4 What cell(s) has these receptors on its surface? What is recognized by these receptors?

12. catalytic SH2 SH2 Src vs. Syk Family Tyrosine Kinases Src Yes Fgr Hck Lyn Blk Fyn Lck Syk - B cells, early T cell development, NK cells, platelets, monocyte lineage ZAP-70 - Throughout T cell development, NK cells B cells T cells

13. Early events in signaling through the TCR - Sequential involvement of src and Syk family src family tyrosine kinases Syk/ZAP-70 family tyrosine kinase

14. Clustering of BCRs initiates signaling into the B cells (receptor aggregation): aggregational signaling In nature, BCR aggregation occurs when an epitope is repeated on one molecule (polymers) or on a surface (e.g., surface of bacteria or virus). Also, conformational signaling; antigen binding to the receptor changes the conformation (3D structure) of the receptor so it gains or looses reactivity; this occurs when epitopes do not repeat on an antigen

15. Sequential tyrosine kinase activation in B cells

16. Multi-domain adaptors nucleate signaling complexes SH2 (src-homology 2) :: phospho-tyrosine SH3 :: proline-rich sequences Different SH2 and SH3 domains have different specificities

29. Negative regulation and down-regulation of TCR and BCR signaling • Internalization; trafficking to endosomes/lysosomes • role for the immune synapse in this process? • Ubiquitination --> proteosomal degradation of receptor • Cbl and other adaptors • Phosphatases - remove tyrosines, etc. • SHP-1 and others