Exam 3: Costimulation, T Cell Anergy, Immunological. Synapse Flashcards
What are the two MHC restriction paradoxes?
Alloreactivity and Superantigens
Describe alloreactivity
When foreign MHC complex is recognized by T cells (1-10% od T cells react this way). T cells view very similar structure (whether peptide dominant or MHC dominant)
Describe superantigens
bacterial and viral proteins that can activate 2-20% of all T cells (all T cells expressing VB gene segments)
Bacterial superantigens are responsible for
toxic shock syndrome
Do superantigens need to be processed?
No
T/F Superantigens are Class I dependent
F. They are Class II dependent
Where to superantigens bind??
Outside of groove in MHC/TCR complex
What is an example of a bacterial superantigen?
Staphylococcal enterotoxin (SE); TSST-1
What is the difference between bacterial and viral superantigens?
Viral superantigens (often from retroviruses) are membrane bound (APC cell membrane); bacterial are soluble
Signal 1
TCR and MHC –> antigen-specific
Signal 2
Co-stimulation from antigen-independent receptor
Where are costimulatory molecules expressed?
APC’s
What are adjuvants?
substance that induce APC to upregulate ligands for co-stim receptors on T cells
What is the most important co-stim molecule expressed on T cells?
CD28!!!
3 properties of CD28
- member of immunoglobulin superfamily (IgV domain)
- Expressed on almost all T cells (all mouse cells; 80% of human T cells) as a disulfide-linked dimer
- Binds to B7-1 (CD80) and B7-2 (CD86) expressed on APC’s (also Ig superfamily members containing one IgV and one IgC domain)
B7-1 is also called
CD80
B7-2 is also called
CD86
What happens when TCR and costimulatory signals are seen?
proliferation and IL-2 production; followed by self-signaling via IL-2
Name the 3 binding motifs associated with CD28
- PI3K
- Grb2
- Irk
NO ITAM
what happens when CD28 is the only signal
Nothing except for activation of PI3K
What are some other costimulatory molecules?
ICOS; CD40; 4-1BB
T/F ICOS is expressed after activation of naive T cells
T
What induces ICOS signal?
CD28 costimulation!
What does ICOS bind to?
LICOS aka ICOSL aka B7RP-1
What is ICOS important for?
IL-4 production
APC or T cell
CD40, 4-1BBL
APC
APC or T cell
CD40L, 4-1BB
T cell
How are CD40/CD40L and 4-1BB/4-1BBL and ICOS/LICOS similar?
Help define differentiation of T cell
determine which cytokines are used
effector or memory cells
sustain T cell activation
CD28 initiates activation, ICOS, CD40, 4-1BB ___
FINE TUNE response
Name an inhibitory co-stimulatory molecule
CTLA-4
How does CTLA-4 inhibit activation?
outcompetes CD28 and binds to B7-1 and B7-2
Why do we need CTLA-4
negative feedback helps prevent too much of an immune response. CTLA-4 amounts high after TCR + CD28 stimulation.
What induces CTLA-4 expression?
activation of naive T cells over time when balance is tipped. Allows immune system to shut down when pathogen is mostly cleared
What is the inactive/tolerant state when T cells are activated without costim?
ANERGY
Why do we have anergenic T cells?
damp down autoimmune reactions; regulatory type T cells
What two things are required for Immunologic Synapse that facilitates T cell response to APC/target cell?
- Reorganization of the T cell to have organelles facing APC
- Lipid raft reorganization so small lipid rafts condense to form larger lipid rafts to facilitate adhesion molecules (ICAM) to provide signaling complex
What molecules facilitate reorganization of T cell?
Vav- a GED
WASp–> activates Arp2/3 complex –> critical for actin cytoskeleton reorientation
