6 - Immune Receptors and Signal Transduction Flashcards
Cytokines
Low weight regulatory molecules (proteins or glycoproteins) secreted by immune cells and various other cells in response to stimuli
Ways of cytokine signalling
- Autocrine (same cell)
- Paracrine (close proximity)
- Endocrine (long distance)
Major categories of signalling receptors in the immune system
- a receptor that uses a non-receptor tyrosine kinase
- a receptor tyrosine kinase
- a nuclear receptor that binds its ligand and can then influence transcription
- a seven-transmembrane G protein–coupled receptor (GPCR)
- Notch, which recognizes a ligand on a distinct cell and is cleaved, yielding an intracellular fragment (IC Notch) that can enter the nucleus and influence transcription of specific target genes.
Non receptor tyrosine kinase-based receptors
- Regulate cell growth, proliferation, differentiation, adhesion, migration and apoptosis
- Mediate cytokine responses
Cytosolic signalling phase of NRTK
- The NRTK phosphorylates a key tyrosine residue on the cytoplasmic tail of the receptor
- The phosphotyrosine-containing receptor tail is able to recruit a downstream enzyme that is activated once its recruited
- Modifies a specific transcription factor that is located in the cytoplasm
Nuclear signalling phase of NRTK
- This modified transcription factor enters the nucleus and binds to a specific site in the promoter or in some other regulatory region of target genes and thus facilitates their expression
- Cytokines are produced by receptor-expressing cell
SRC family kinases
Immunologically important family of nonreceptor tyrosine kinases
c-SRC
- Cellular homolog of the transforming protein of the Rous sarcoma virus
- c-SRC contains several distinct domains, two of which, called SRC homology 2 (SH2) and SRC homology 3 (SH3) domains, mediate binding to other signaling proteins
FcγRIIB
Inhibitory receptor found on B cells and myeloid cells
Activating and inhibitory Immune receptors
- Immune receptors that activate immune cells have separate polypeptide chains for
recognition, and associated polypeptide chains that contain cytosolic ITAMs (immunoreceptor tyrosine activation motif) - Inhibitory receptors in the immune system typically have ITIMs on the cytosolic portion of
the same chain that uses its extracellular domain for ligand recognition
Structure of T cell receptor
- The antigen-binding portion of the TCR is formed by the Vβ and Vα domains.
- The hypervariable segment loops that form the
peptide-MHC binding site are at the top
TCR complex
- The CD3 and ζ proteins are noncovalently associated with the TCR αβ heterodimer to form the TCR complex
- When the TCR recognizes antigen, the associated
proteins transduce the signals that lead to T cell activation
CD3 and ζ proteins
- Identical in all T cells regardless of specificity, showing their role in signalling and not antigen recognition
- Required for surface expression of the complete receptor complex on T cells
Which cells express CD3
T cells
Other T cell receptors (besides TCR)
- CD3
- CD4
- CD8
- CD28
- CTLA-4
- PD-1
- LFA-1
CD3
- Signal transduction by TCR complex
- No ligand
CD4
- Signal transduction
- Ligand: Class II MHC expressed on APCs
CD8
- Signal transduction
- Ligand: Class I MHC on all nucleated cells
CD28
- Signal transduction (costimulation)
- Ligand: B7-1/B7-2 on APCs
CTLA-4
- Inhibition
- Ligand: B7-1/B7-2 on APCs
PD-1
- Inhibition
- has an immunoreceptor tyrosine-based switch motif (ITSM) in its cytoplasmic domain
- Ligand: PD-L1/PD-L2 on APCs, tissue cells and tumor cells
LFA-1
- Adhesion
- Ligand: ICAM-1 on APCS and enothelium
Early tyrosine kinase phosphorylation events in T cell activation
- On antigen recognition, there is clustering of T cell receptor complexes with coreceptors
- CD4-associated LCK becomes active and phosphorylates tyrosines in the ITAMs of CD3 and ζ chains
- ZAP70 binds to the phosphotyrosines of the ζ chains and is itself phosphorylated and activated.
- Active ZAP70 then phosphorylates tyrosines on
various adaptor molecules (such as LAT)
The immune synapse
supramolecular activation cluster (SMAC)
- When the TCR complex recognises MHC associated peptides on an APC, several T cell surface proteins and intracellular signalling
molecules are rapidly mobilized to the site of T cell–APC contact - PKC is a protein kinase involved in signal transduction
- Integrins LFA-1 and talin function to stabilise binding of the T cell to antigen presenting cell, APC
MicroRNAs (miRNAs)
- miRNAs are small noncoding RNAs that are transcribed from DNA but are not translated into proteins
- Act to inhibit gene expression
- One strand of the miRNA can pair with a complementary sequence in a number of cellular messenger mRNAs
B cell receptor complex
Membrane immunoglobulin (IgM and IgD) on the surface of mature B cells is associated with the invariant Igβ and Igα molecules, which contain ITAMs in their cytoplasmic tails that mediate signalling functions
Cytoplasmic tail of membrane IgG
Contains a Ig tail tyrosine (ITT) motif that helps amplify B cell receptor signalling in memory B cells.
Antigen-induced cross-linking of membrane immunoglobulin (Ig) on B cells
- Clustering and activation of SRC family tyrosine kinases and tyrosine phosphorylation of the ITAMs in the cytoplasmic tails of the Igα and Igβ molecules
- Leads to docking of SYK and subsequent tyrosine phosphorylation events
- Signaling cascades follow these events leading to the activation of transcription factors
- Signal transduction pathways are similar to those
described in T cells
Role of complement in B cell activation
- B cells express a complex of the CR2 complement receptor, CD19, and CD81
- Microbial antigens that have bound the complement fragment C3d can simultaneously engage both the CR2 molecule and the membrane immunoglobulin (Ig) on the surface of a B cell
- This leads to the initiation of signalling cascades from both the B cell receptor complex and the CR2 complex:
- The response to C3d-antigen complexes is greatly enhanced compared with the response to antigen alone.
Role of the ubiquitin ligase CBL-b in terminating T cell responses
- facilitates the ubiquitination of CD3, ZAP70, and other proteins of the TCR complex
- These proteins are targeted for proteolytic degradation
Extracellular and intracellular portions of cytokine receptors
All cytokine receptors consist of one or more transmembrane proteins whose extracellular portions are responsible for cytokine binding and whose cytoplasmic portions are responsible for initiation of intracellular signaling pathways
RNA induced silencing complexes (RISC)
In the cytosol, pre-miRNAs are processed by endoribonuclease Dicer into short double-stranded miRNAs, 21 to 22 base pairs in length, which associate with several proteins, including Argonaute, to form a RISC
What does ligation of receptors for type 1 and 2 cytokines result in
- Activation of an associated JAK tyrosine kinase
- Phosphorylation of the receptor tail
- Recruitment of an SH2 domain, containing activator of transcription (STAT) to the receptor
JAK-STAT signalling
- Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called STATs
- The recruited STAT is activated by JAK phosphorylation, dimerizes, enters the nucleus, and turns on the expression of cytokine target genes
CD3 structure
- CD3 γ, δ, and ε and the ζ homodimer.
- The CD3 chains each contain one ITAM, whereas each ζ chain contains three ITAMs
