Innate TLR signaling :
IRAK-M: interleukin-1-receptor associated kinase M SOCS1: suppressor of cytokine signaling 1. MyD88s: myeloid differentiation primary-response protein 88 short SIGIRR: single immunoglobulin IL1R-related molecule Negative Feedback!
NKG2D
ITAM Syk.. (DAP12)
Activating receptors mediate cellular activation
Regulation by Inhibitory receptors
•B cell, mast cell: FcRIIB，PIRB Cross-linking immune complex or antiidiotype antibody with BCR •T cell: CTLA-4, PD-1 CTLA-4 and PD-1 transmit signals that inhibit lymphocyte activation, providing a pathway of classical feedback inhibition. •NK, CTL: KIR，Ly49 (type I), CD94/NKG2A (type II)
Toll-like receptor signaling pathways
MyD88 pathway and TRIF pathway; Transcription factors Cytokine expression
Innate response is critical for an effective immune response. Excessive response lead to endotoxic shock (sepsis)： Sepsis（败血 症） is a serious medical condition that is characterized by a wholebody inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence of a known or suspected infection. The body may develop this inflammatory response to microbes in the blood, urine, lungs, skin, or other tissues. A lay term for sepsis is blood poisoning.
Regulation by Inhibitory receptors
Cell type Activation activati Trigger on motif
BCR
Kinase recruited
B cell
ITAM Lyn (Ig Ig)
T cell
TCR
ITAM (CD3)
Lck
NK cell
Regulation by Inhibitory receptors
1). Activating receptor:
Two type of receptors
ITAM (immunoreceptor
tyrosine-based activation motif) Motifs：YxxL/V
Recruit : kinases, adaptor proteins
The Key event for innate immune response: Recognition of microbe patterns by pattern recognition receptors including TLR.
Regulation of TLR4 signaling
Immunoregulation
Immune Response and Regulation: Including Positive & Negative regulation. Positive regulation ensures fast response. While negative regulation after the clearance of infection is very essential for restore the immune homeostasis. Immunoregulation and intervention: Upon the understanding of immunoregulation mechanisms, we can deliberately enhance or take away one of the control to enhance or block an immune response (Tumor or Transplantation rejection ). Immunoregulation and Disease: Since immune regulation is achieved at many different levels by different mechanisms, any defect in this system will cause an immune disorder.
Immune regulation happens at different stages of an immune response
During Innate Immune Response TLR mediated inflammatory response Cytokine signaling During adaptive immune response By Inhibitory receptors By Tregs Other Immune regulation mechanisms Regulation by antibody by the idiotype and anti-idiotype network
Inhibitory receptors
Inhibitory receptors on B cell
Once the ITIM of FcRIIB is phosphorylated, SH2containing SHIP are recruited, which influences PI3K and ERK pathways. PIRB（paired immunoglobulin-like receptor B ） ITIMs recruites SHP1， which dephosphorylates various protein-tyrosine kinases, including SYK and Bruton's tyrosine kinase (BTK).
Immune Response
Toll-like receptors and recognition of pathogens
K. Takeda & S. Akira, Cell. Microbiol. 5: 143-53, 2003 diacyl- triacyl-lipopeptide 酰基脂肽；flagellin:鞭毛蛋白; LPS:脂多糖 (Lipopolysaccharides)
Inflammatory cytokines
TLR4 signaling is regulated by membrane trafficking: Rab10 Rab7b promote endocytosis and degradation Cao X 2007 Rab10 promote trafficking onto cell surface. Wang D et al in Lu lab 2010
Regulation by signaling pathways (cytokine receptors signaling)
Regulation by signaling pathways (SOCS family)
Summary of the first part: Regulation of TLR signaling The role of SOCS in cytokine signaling (inducible, ubiqutin ligases)
Inhibitory receptors
Inhibitory receptors
Inhibitory receptors for T cell. CTLA-4
Y201 YVKM Y208
Inhibitory receptors
Dynamic regulations of T cell activation by CD28 and CTLA4: 1. CD28 and CTLA-4 has the same ligand B7. 2. Resting T cell only express CD28, which is an activating coreceptor provides 2nd signaling to ensure T cell activation. 3. Activated T cells start to express CTLA-4 on their surface, because CTLA-4 has 100 folder higher affinity to B7, CTLA-4 activation become dominant which inhibit the TCR signaling. 4. CTLA-4 Ig Before activation After activation