The Life of a T Cell- Mobilizing the Troops Flashcards
What cell is the most populous in the spleen?
What other cells are present?
What cell is the minority in the spleen?
Mostly B cells
Other cells:
- macrophages
- dendritic cells
- NK cells
- NK T cells
T cells are in the minority in the spleen
How many different peptides can an HLA molecule bind?
How many can T cells recognize?
HLA can present 1000s of different peptides as long as they are similar structurally
T cells can recognize a subset of these peptides
What are the 3 secondary lymphoid organs T cells will go to after they mature in the thymus?
- Spleen
- Lymph node
- Peyer’s patch
Deviations from lymphocute levels are a red flag for:
- infections
- malignancies
- autoimmune disorders
- immunodeficiencies
A CD4 count of less than __________ is a diagnostic indicator of ________________ and the person is of immediate concern for __________________ infections.
400
HIV
opportunistic
What virus targets CD4 T cells specifically?
HIV
What percent of T cells are DP in the peripheral lymphoid organs?
0%
What is the normal ratio of CD4 Tcells to CD8 T cells?
1.5/1 or 2/1
there are usually the least NK cells
When a T cell leaves the thymus as a positively-selected CD4 SP or CD8 SP T cell, what is it called? Why?
It is a naive T cell still because it won’t be considered mature until it encounters an antigen in the secondary lymphoid organ
Naive T cells can only be activated once they receive three signals. What are they?
- TCR interacting with APC/Macrophage/DC
- CD28 costimulatory molecule (ICOS)
- Cytokine receptor
When a naive T cell is activated with the 3 signals, what does it become?
an “effector” T cell
Are the three activation signals (TCR/APC, CD28, cytokine receptors) required to activate a memory T cell?
nope
Where do the three signals to activate a T cell occur?
secondary lymphoid organs following T cell interactions with professional APCs
How does a naive T cell enter the secondary lymphoid organ? What signals are involved?
L-selectin on the T cell binds to GlyCAM or CD34 on the HEV of the lymph node (or MadCAM on mucosa to enter Peyer’s patches)
Once in the lymph node or spleen, how is the T cell directed into PALS or perifollicular areas that are rich in T cells?
chemokine/cytokine receptor interactions
What is the best APC to present to T cells in lymph nodes and the spleen? How does this cell arrive in LN or spleen?
dendritic cells which arrive via lymphatic drainage
(T-cells get into the LN or spleen via blood)
What are the four adhesion molecules on the T cell that allow it to attach to the APC?
LFA-1, VLA-4, ICAM-1, CD2
What does LFA1 on the Tcell bind to on the APC?
ICAM on the APC
What does ICAM on the T cell bind to on the APC?
LFA1 on the APC
What does VLA-4 on the T cell bind to on the APC?
VCAM
What does CD2 on the T cell bind to on the APC?
LFA3
What do the interactions driven by the adhesion molecules between T cells and APCs allow to happen?
The T-cell can sample the peptide/HLA molecules on the APC
What is the addressin, cytokine receptor and chemotactic factor on the T cell that bring it into the lymph node?
L-selectin
CCR7
CXCR4
How many foreign agonist peptide/HLA complexes must be on an APC for a TCR to detect it and be activated?
3-5
What is the “immunological synapse”?
The clustering of TCR on the T cell and foreign peptide/HLA on the APC to allow 3-5 HLA complex to be together to activate the T-cell?
What are TCR in immunological synapses able to do?
Signal and internalize what the HLA/foreignpeptide is presenting and engage more TCRs with the same 3-5 agonist peptide/MHC complexes.
What occurs at the interface of TCR and HLA molecules on the APC?
Immunological synpase where the TCR can
- receive signals
- Recycle
- Serially engage the APC
What is the role of CD28 when a Tcell meets an APC?
It is a constimulatory molecule that binds B7-1/B7-2 on the APC to elicit a signal cascade (SIGNAL 2)
Due to its short cytosolic tail, abTCR is unable to efficiently signal into the T-cell. What must it associate with?
CD3 epsilon/delta and gamma/epsilon and zeta/zeta subunits
When the TCR is engaged by an antigen, what is the first step in the signal transduction pathway? (what molecule is activated and what is its function?)
LCK tyrosine kinase is activated and phosphorylates the ITAMs on the CD3 subunits
When ITAMs begin being phosphorylated by the LCK tyr-kin, what other kinase is recruited and what is its function?
ZAP-70 phosphorylates LAT (“linker of activated T cells”)
What is LAT?
Linker of Activated T-cells. It is stimulated by ZAP70 and serves as a docking site for PLC-gamma (phospholipase C) which increases intracellular calcium.
Why is it important for intracellular calcium to go up in T-cell transduction pathway?
Ca activates the calcineurin signaling molecule which activates various transcription factors (NFKb, NFAT, MAPK)
What structure on the APC binds to the CD28 molecule on the T-cell?
B7-1/B7-2 (also called CD80/CD86)
What three transcription factors are elicited by T-cell signal transduction?
NFAT, NFkB, MAP kinases
What drug inhibits calcineurin shutting off T-cell activation? What is this drug used for?>
Cyclosporine is used as an immunosuppressant to help with transplant rejection
What two drugs are currently FDA approved as immunosuppressants to help with transplant rejection?
FK506 and cyclosporine
What 5 antigen binding receptors use Src family tyrosine kinases to transmit signal in their cells?
TCR (CD3) BCR (Iga, Igb) NK activating receptor (DAP12) Fc Receptor (FcgammaRIII) Neuronal receptors (CD3 zeta and epsilon)
What costimulatory molecule is responsible for “signal 2” in T-cell activation?
CD28 which binds to two surface molecules (b7-1/b7-2 aka CD80/86) on the antigen presenting cell
When CD28 on the T-cell binds to CD80/86 on the APC, what happens next?
The CD28 cytoplasmic tail gets phosphorylated at its tyrosine residues allowing PI3K to associate with it and initiate the activation of additional proteins
What associates with the CD28 molecule when it has been phosphorylated?
PI3K
When signal 1 and 2 on the T-cell converge on NF-kB, what occurs?
NFkB translocates to the nucleus to transcribe and release IL-2.
If a naive T cell receives a strong signal1, but no signal two, what happens?
It is not activated and becomes functionally impaired (anergy)
What 4 changes in cell surface proteins occur upon T-cell activation?
- increased chemokine receptors
- up-regulation of CD40L (used to activate B cells)
- Increased SIP1
- expression of IL-2 receptor, CD25
What is IL-2?
What does it bind to when it is operating in an autocrine fashion?
A growth factor that supports T-cell division.
When it is working in an autocrine fashion, it binds to CD25 on the T-cell surface
When IL-2 is working in a paracrine fashion, what does it bind to and what is its function?
It works to help the CD8 cells expand
What is the function of CD40L?
It helps T cells interact with B cells and macrophages to help activate them
Mutation to CD40L results in what?
Failure of T and B cells to interact which means that they cannot class switch or go through somatic mutation and leads to Hyper-IgM
Signal 1 and 2 are most important for cell__________.
Signal 3 is required to give the cell __________.
growth and expansion
function
What provides signal 3 to the T-cell?
cytokines and chemokines
What is S1P1?
What drug can block its expression?
it is a cell surface molecule on the T-cell that allows it to leave LN and thymus to go to the target tissue.
It is blocked by FTY720
