MCM 2-8 T-Cell Immunity Flashcards
Where is a naive T cell activated?
What 2 signals are required to activate a naive t-cell?
via exposure to an antigen, occurs in a lymph node that is draining an infected tissue.
2 signals required:
- an antigen specific signal - delivered when the T-Cell receptor recognizes the peptide:MHC complex on the dendritic surface
-a costimulatory signal: delivered when cd28 on T-cell surface binds to B7 on dendritic cell surface (B7 is expressed in activated APC’s)
What happens if a naive T-cell enters an uninfected lymph node
it will return to circulation and continue to enter and exit unchanged until it enters an infected one
What is the only antigen presenting cell that can present to a naive T-cell? why?
dendritic cell. they constitutively express both MHCII and B7
Macrophages must be activated to express MHCII and B7
B cells must be activated to express B7
CD28-mediated co-stimulation is not required for the stimulation of which types of cells?
Why is this?
effector T cells and memory t cells.
because they have already been selected for antigen specificity so the stringent requirement for co-stimulation is not necessary.
Do not need to be presented with B7.
Gamma/Delta T cell activation is CD28 independent
what drives the activated T-cells differentation and proliferation?
autocrine production and uptake of IL-2.
Naiive T cells - moderate IL2 affinity
Activatated T-cells - strong affinity IL2
uptake of the IL2 they produce can allow them to differentiate into effector or memrory cells
structural changes that occur when a T-cell becomes activated?
change in distribution of cell surface molecules/receptors
lose molecules that cause them to remain in lymph node
gain adhesion molecules/receptors on surrface allowing tehm to interact with other cells that express the ligand to those receptors -> helps them interact with other cells and hones them to other tissues where they are needed. You can generate T-Cells that target every tissue in the body this way.
CD4+ TH1 cells
activated t-cells become TH1 cells in presence of IFN-Gamma and IL12.
produce transcription factor T-Bet
Produce cytokines IL2 and IFN gamma
function to activate macrophages
CD4+ TH2 Cells
become TH2 in presence of IL-4.
PRoduce transcription factor GATA3
Produce cytokines IL4 and IL5
function to activate cellular and antibody responses to parasites
describe the balance of TH1 and TH2
balance is important. TH2 can inhibit macrophages, thus preventing the necessary response.
if TH2 is overproduced when TH1 should be produced (as in a bacterial or viral infection), this can lead to disseminated infection.
-This occurs with leprosy. The mild tuberculoid form occurs in those who can mount the proper TH1 response and rally macrophages. the severe leproid form occurs when the patient is unable to mount the proper TH1 response and instead responds with TH2.
CD4+ TH1 and TH2 clear pathogens
indirectly by interacting with effector cells that clear pathogens
function of CD8+ T-cells
kill infected target or tumor cells directly by apoptosis and cytokine exposure
1. granule exocytosis (fast, predominant) - arrange their organelles to deposit granzymes and perforin towards the infected cell.
- Apoptosis (slow)
- caspace actiavtion which causes DNA fragmentation
- mtochondrial damage causes cytochrome C release
they also secrete INF-Gamma like the TH1 cells do, but CD8+ cells do it not to kill via macrophage but have the macrophage clean up the debris
why are CD8+ cells so stringently activated?
they can cause lots of damage, potentially acting on every cell in the body and causing massive tissue damage.
The activation of CD8+ t-cells may or may not require..
CD4+ TCell help, which secretes IL2 which causes the CD8 to proliferate
how is the immune response “turned off” after an infection is cleared?
Mainly by the expression of CTLA-4 by activated t-cells. this molecule has a higher affinity for B7 than cd28 does. Once bound to the B7 of presenting cells, stops additional activation and sends inhibitory signals to T-cell
Also once antigen is cleared, there is no antigen to present to T-cells and activate them
defects in CTLA-4 can lead to
autoimmune diseases such as lupus. T-cells and immune response doesnt shut off correctly.
what is belatacept?
a prescription form of CTLA-4. Given to kidney transplant recipients to shut down t-cells that may have been activated by the transplant.
anergy
prevention of T-Cell activation, generally via CTLA-4 or prescription form belatacept.
Lupus treatment
molecules that target defective CTLA-4.
4 ways to turn off immune response
CTLA-4 elimination of antigen elimination of other stimuli Tregulatory Effectors killing by immunoregulatory cells
where are dendritic cells found? how can they take up antigen?
mostly in epithelial CT, by pino or phagocytosis
dendritic vs macrophage vs b-cell presentation
dendritic cells provide a strong Co-stim, and always have MHCII and B7. They are important in stimulating naiive T-cells
Macrophages and B-cells are important in presentation later on in infection when presenting to mature effector T-cells
b-cells and macrophages express lower levels of MHC and other stimulatory molecules
CD4 differntiation in a viral/bacteria infection
first cytokine produced is IFN-gamma and macrophages will express IL12. In the prescence of these two signals, T cells differentiate into TH1
CD4 differentiation in parasitic environment
you’ll have production of IL4 from basophils and mast cells, driving differentiation towards TH2
TH17
produces IL17, enhances neutrophil response (inflammatory)
Tfh
stay in lymph node, unique, activate B-cells and maturation of antibody response including switch response. IL21
Treg
produces TGF-Beta cytokine that is suppressive, turns off immune system
expresses FOXP3 - suppresses effector cells and antigen presenting cells
for lymphocyte to turn to a plasma cell, what is needed?
interaction with TH2 CD4+ T-cell
cognate interaction between cd40 ligand and cd40 requires production of cytokine and binding of bcell receptors to turn plasma cell and secrete antibody to neurtalize antigen
main goal of CD4+ TH1 cells?
bring various cells of immune response into area of infection and remove infection
produce LOTS of different cytokines, mostly inflammatory
-excrete INFgamma and have cd40 ligand to activate macrophages
-can express FAS ligand which leads to killing of infected cells
-produce il2 to induce proliferation of more t-effector cells
Produce il3 to induce macrophage differentiation in bone marrow
Produce TNFalpha and TNFbeta to activate epithelium so macrophages can exit into tissues
Cxcl2 - chemokine causes macrophages to accumulate at site of infection
what organizies the cellular components of the CD8+ cell when it wants to align its organelles to kill?
MTOC, microtubules
benefit of CD8+ inducing apoptosis?
by having cell self-destruct and not lyse, you prevent spread of pathogen. The nucleases not only degrade the cellular DNA but also degrade the pathogen as well. This process helps contain the infection while it is killed.
rate limiting step in CD8 Killing?
time it takes to synthesize granules.
antigen presented by dendritic cells?
peptides, viral antigens, allergens
antigen presented by macrophages?
particulate antigens, intracellular/extracellular pathogens
antigen presented by b-cells?
soluble antigens, toxins, viruses
how do naiive t-cells enter the lymph node?
by two routes
- in the blood
- or in the afferent lymph coming from an upstream lymph node
what directs activated t-cells to distinct anatomical sites?
differential expression of adhesion molecules
what is critical to the ability of CD4+ T-cells to activate other cells?
the CD40 ligand
the interaction between a b cell and t-cell with specificity for the same antigen is called
cognate interaction
effector functions of CD4+ TH1 cells
IFN-Gamma FAS ligand+TNF beta IL2 IL3 + GM-CSF TNF-A,B CXCL2
IFN-gamma + cd40 ligand = activates macrophages to destroy engulfed bacteria
FAS ligand + TNF-beta - kills infected macrophages, releasing bacteria to be destroyed by healthy macrophages
IL2 - induces T-cell proliferation, increasing the number of effector T-cells
IL3 +GM-CSF = induces macrophage differentiation in bone marrow (increase macrophage population)
TNF alpha and TNF beta = activates endothelium to induce macrophage adhesion and exit from blood vessel at site of infection
CXCL2 = causes macrophages to accumulate at site of infection
At an infection site you measure a large amount of IL-12 and IFN-gamma…what class of effector CD4+ t cell will this induce?
What function will that effector t cell perform?
IL-12 and IFN-gamma induce TH1 cells to form and it will activate macrophages at that site.
At an infection site you measure a large amount of IL-4…what class of effector CD4+ t cell will this induce?
What function will that effector t cell perform?
IL-4 induce TH2 cells and they will activate cellular and antibody response to parasites
Which characteristic cytokines do TH1 and TH2 cells produce?
TH1 cells produce IL-2 and IFN-gamma
TH2 cells produce IL-4 and IL-5
what controls migration of naiive T-cells into and out of lymph nodes?
selectins, integrins, and chemokine receptors expressed on T-cells
if a t-cell encounters pathogen antigens, they are activated and leave as effector cells
clonal expansion is driven by
high affinity I2 receptor and autocrine IL2 excretion
what directs activated T-cells to distinct anatomical sites?
differential expressions of adhesion molecules
what induces T-reg differentiation? what do they make?
TGF-beta
tgf-beta and IL10(to inhibit actiavted T-cells)
