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
