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Immune%20Receptors%20%20and%20Signal%20Transduction

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Title: Immune%20Receptors%20%20and%20Signal%20Transduction


1
Immune Receptors andSignal
Transduction
  • Chapter 7

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  • The idea that cells may have specific surface
    receptors that can be triggered by external
    ligands came from one of the founders of modern
    immunology. Paul Ehrlich, in his side chain
    theory, published in 1897, conceived of
    antibodies on the surface of immune cells that
    recognize antigens and instruct the immune cell
    to secrete more of the same antibody. Cell
    surface receptors for hormones were discovered
    many decades later in the second half of the 20th
    century but well before the identification of
    antigen receptors on lymphocytes in the early
    1980s

4
  • Cell surface receptors serve two major functions
  • the induction of intracellular signaling and
  • the adhesion of one cell to another or to the
    extracellular matrix
  • Signaling initiated by these receptors typically
    involves an initial cytosolic phase when the
    receptor or proteins that interact with the
    receptor may be post-translationally modified.
    This often leads to the activation or nuclear
    translocation of transcription factors that are
    silent in resting cells, followed by a nuclear
    phase when transcription factors orchestrate
    changes in gene expression
  • Signal transduction result in a number of
    different consequences for a cell, including
    acquisition of new functions, induction of
    differentiation, commitment to a specific
    lineage, protection from cell death, initiation
    of proliferative and growth responses, and
    induction of cell cycle arrest or of death by
    apoptosis

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Signaling from the cell surface involves
cytosolic and nuclear phases
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  • AN OVERVIEW OF SIGNAL TRANSDUCTION

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  • The initiation of signaling from a cell surface
    receptor may require ligand-induced clustering of
    the receptor, known as receptor cross-linking, or
    may involve a conformational alteration of the
    receptor that is induced by its association with
    ligand
  • The enzymes that add phosphate groups onto amino
    acid side chains are called protein kinases
    (protein tyrosine kinases)
  • Other protein are serine/ threonine kinases,
  • Some enzymes activated downstream of signaling
    receptors phosphorylate lipid substrates they
    are therefore known as lipid kinases
  • specific phosphatase,

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  • Cellular receptors are grouped into several
    categories based on the signaling mechanisms they
    use and the intracellular biochemical pathways
    they activate

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Modular Signaling Proteins and Adaptors
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The modular structure of tyrosine kinases that
influence lymphocyte activation
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  • THE IMMUNE RECEPTOR FAMILY

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Immunoglobulin (Ig) superfamily
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T Cell Receptor Complex and T Cell Signaling
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Ligand-receptor pairs involved in T cell
activation
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Co-receptors
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Immunologic Synapse
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Early tyrosine phosphorylation events in T cell
activation
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  • Activation of Transcription Factors That Regulate
    T Cell Gene Expression

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Co-stimulatory and Inhibitory Receptors of the
CD28 Family
  • CD28 is a membrane protein that transduces
    signals that function together with signals
    delivered by the TCR complex to activate naive T
    cells
  • In the case of T cells, binding of peptide-MHC
    complexes to the TCR (and to the CD4 or CD8
    coreceptor) provides signal 1. The second signal
    for T cell activation is provided by molecules
    that are collectively called costimulators
  • Best defined costimulators for T lymphocytes are
    a pair of related proteins, called B7-1 (CD80)
    and B7-2 (CD86), that are expressed on dendritic
    cells, macrophages, and B lymphocytes

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Costimulatory Receptors of T Cells
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  • Structure of the B Cell Receptor for Antigen

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Metabolic changes during T cell activation
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  • THE ATTENUATION OF IMMUNE RECEPTOR SIGNALING

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Inhibitory signaling in lymphocytes
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E3 Ubiquitin Ligases and the Degradation of
Signaling Proteins
36
  • The prototypical inhibitory receptor of the CD28
    family, CTLA-4 (also called CD152), has the
    ability to inhibit T cell responses induced on
    activated T cells and has a higher affinity than
    CD28 for B7 proteins. CTLA-4 is involved in the
    maintenance of unresponsiveness (tolerance) to
    self antigens
  • Another inhibitory receptor of the same family is
    called PD-1 (programmed death 1)
  • CTLA-4 contains a tyrosine-containing motif in
    its tail that may be inhibitory PD-1 contains
    cytosolic ITIM (Immunoreceptor tyrosine-based
    inhibition motif) and ITSM (Immunoreceptor
    tyrosine-based switch motif) motifs, and its
    cytosolic tail is critical for the initiation of
    inhibitory signals
  • The key inhibitory receptors in B cells include
    Fc?RIIB and CD22/ Siglec-2

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  • CYTOKINE RECEPTORS AND SIGNALING

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Classes of Cytokine Receptors
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JAK-STAT Signaling
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