L11: T Cell Activation Flashcards
What are the phases of T cell responses?
Antigen recognition Activation Clonal expansion Differentiation Effector functions
During the activation phase of T cell response, what causes proliferation or expansion?
Upregulation of IL-2 receptor on the T cells and upregulation of production of IL-2
CD3 molecules
T cell receptors are always non-covalently associated w/ CD3 molecules
There are different subunits of CD3, but all are non-covalently associated
ITAMs
Immunoreceptor tyrosine-based activation motif
This motif has signaling function
Is on the chains of CD3
Other receptors of the immune system also have one or more ITAMs associated
After there is antigen recognition, there isphosphorylation of ITAMs on the TCR as well as the CD3 molecule, which recruits another kinase to it
What is ZAP-70? (not what does it do)
Whole complex of ITAMs w/ kinase
This is one of the initial transcription factors involved after a T cell recognizes self-MHC and a foreign antigen
What are the 2(+1) competence signals for T cells?
- MHC+peptide
- Co-stimulation
- Cytokines
B7
Family of co-stimulators on an antigen present cell
CD28
Co-stimulator receptors on T cell
What causes initial phosphorylation of ITAMs? What results?
When TCR recognizes self-MHC and foreign peptide and CD28 recognizes a B7 molecule
This ultimately leads to production of IL-2 which leads to T cell proliferation and differentiation into effector cells; this is clonal expansion bc this one T cell is going to multiply many times
What does ZAP-70 do?
Phosphorylates LAT and SLP-76, initiating 4 downstream signaling molecules
Ultimately leads to activation and transcription of 3 important transcription factors: NFAT, NF-κB, and AP-1
What do NFAT, NFκB, and AP-1 do?
Bind to the promoter region of IL-2
Induce IL-2 gene so IL-2 is secreted; this happens very quickly since want proliferation to happen very quickly as well
What is difference in IL-2 receptor b/w naive and activated T cell?
Naive T cell: Part of IL-2 receptor is expressed (have the β and γ chains); have a moderate affinity for IL-2
Activated T cell: Once T cell recognizes foreign peptide, it becomes activated and expresses α chain (in addition to β, and γ chains); IL-2 receptor has high affinity for IL-2
IL-2
A cytokine that is a T cell growth factor
Is an autocrine bc it is produced by the T cell and has an effect on the T cell
What signals the T cell to enter the cell cycle?
Binding of IL-2 to its receptor
How much IL-2 is required to activate T cells?
100x more IL-2 required to activate naive vs. activated T cells
Activation of TH cell by what upregulates expression of IL-2?
Both signal 1 and costimulatory signal 2
What does upregulation of IL-2 and the IL-2 receptor lead to?
Proliferation
When does T cell division begin? How long is each cycle?
T cell division begins within 18 hours after activation
Each cycle takes about 6 hours
What leads to anergy?
Failure to deliver signal 2
Won’t have transcription of IL-2 and these cells will be anergic
What occurs in anergy?
Cells won’t actually die but will be circulating until normal death due to lifespan
What occurs when an anergic T cell encounters an APC that can deliver both signals?
The anergic T cell still cannot respond
Angergic T cell can’t be rescued
What does requiring 2 signals for T cell activation do?
Reduces anti-self reactivity
Prevents unnecessary T cell activation since failure to co-stimulate leads to anergy
What does co-stimulation lead to?
Upregulation of IL-2 production → 100-fold more IL-2 to activate the naive T cells →
increased transcription of IL-2 gene, increased stability of transcript, anti-apoptotic signals so that T cells survive
Compare activation of naive vs. activated T cells
Naive: have a higher threshold of activation, primarily activated in lymphoid organs (primarily LN), primarily activated by DC, which delivers both MHC-AG and co-stimulation signals
What is the best APC for naive T cell activation?
Dendritic cells
Where does activation of activated T cells occur? Of naive T cells?
Naive: lymhoid organs (primarily lymph node)
Activated: at site of infection
What gene expression occurs immediately following TCR ligation?
Immediate genes:
Expressed within half an hour
Transcription factors: c-Fos, c-Myc, c-Jun, NFAT, and NF-κB
These are immediately expressed so IL-2 is produced and T cells begin to expand
What early genes are expressed following TCR ligation?
Early genes: 1-2 hours; IL-2, IL-2R, IL-3, IL-6, IFN-γ
What late genes are expressed following TCR ligation?
Late genes: >2 days
Adhesion molecules (which will stabilize binding of the effector cell to the infected cell)
Do the APCs constantly produce B7?
Dendritic cell: constitutive B7
Macrophage: inducible B7
B lymphocytes: inducible B7
What leads to expression of APC?
CD40:CD40L co-stimulatory pair
Where is CD40 expressed?
On APC
Where is CD40L expressed?
On T cell
Is expressed following T cell recognition of antigen and self-MHC and CD28 to B7 signal
What does CD40:CD40L cause?
Increased expression of B7, which enhances costimulation
T cells also secrete T cell-activating cytokines
CTLA-4
A negative regulator of an immune response that is also expressed on the T cell
Has a higher affinity than CD28 for B7 and engages it in a multivalent orientation
What has a higher affinity than CD28 for B7?
CTLA-4
Describe formation of the immunological synapse
Before stimulation, the receptors are randomly assorted in the membrane → molecules on both the APC and T cell move together → the organized immunological synpase is formed; consists of the central and peripheral supramolecular activating complex (cSMAC and pSMAC)
Helpful bc all of the cytokine secretion will occur within this synapse
Calcineurin
Critical for activation of NFAT
Cyclosporin
Very potent immunomodulatory drug
Used commonly for transplantation and treatment of immune disorders
Acts on calcineurin and thus inhibits NFAT and downregulates immune response
FK506
Very potent immunomodulatory drug
Used commonly for transplantation and treatment of immune disorders
Acts on calcineurin and thus inhibits NFAT and downregulates immune response
ZAP-70 tyrosine kinase deficiency
Leads to a type of SCID (severe combined immunodeficiency disease)
Bruton’s (X-linked) agammaglobulinemia
Caused by a defect in Btk
X-linked hyper-IgM
Caused by mutation in CD40L on T cells
What is an example of how cytokines transduce signals?
Through JAK/STAT pathway
What does cytokine signaling result in?
Results in induction of genes with appropriate response elements
What does a cytokine being pleiotropic and redundant mean?
Pleiotropic: can act on many different cell types
Redundant: certain cytokines have similar functions
What can deficiency in cytokine signaling lead to?
Immunodeficiency
What kind of cytokine receptor families are there?
Homodimeric receptors
Heterodimeric receptors w/ a common chain
Heterodimeric receptors (no common chain)
TNF receptor family
Chemokine receptor family
Describe signaling through cytokine receptors?
Cytokine receptors consist of at least 2 chains, the cytoplasmic domains of which bind Janus kinases (JAKs) → cytokine binding dimerizes the receptor, bringing together the cytoplasmic JAKs, which activate each other and phosphorylate the receptor → Transcription factors (STATs) binds to the phosphorylated receptors and are in turn phosphorylated by the activated JAKs → phosphorylated STATs form dimers that translocate into the nucleus to initiitate new gene transcription
How does the interferon (IFN) family of cytokines signal?
There are different receptors for Type I, II, and III IFNs, but all involve JAK/STAT
Also involves a series of different transcription factors called interferon response factors (IRFs) that bind to interferon response elements (ISREs) in promoter regions of certain genes
What is IL-2R gamma chain shared by?
IL-2, -4, -7, -9, -11, and -15R
What does lack of IL-2R gamma chain cause?
Defective signaling through IL-2Rs
Since IL-7 is also needed for lymphocyte development, this deficiency therefore results in X-linked SCID
