MMBIO Test 2

What are the TCR light chains?

Alpha and Gamma

What are the TCR heavy chains?

Beta and Delta

Where is the variable region of the TCR

On top to bind antigen

What must the binding region of the TCR regonize before activation?

Antigen and MHC

How are the genes ordered that encode for the TCR?

VDJC for heavy and VJC for light

In what order do the TCR genes rearrange?

Beta, delta and gamma rearrange first

Which chain is more likely to win the rearrangement race?

Beta chain

What happens if a successful beta chain is produced?

Cell attempts rearrangement for alpha chain

Where are the delta genes found?

Flanked on either side with alpha light chain genes

Why is the beta chain more likely to win?

The delta chain has more D boxes which could risk failure in recombination and both delta and gamma need to be successful rather than just beta.

Are TCRs ever secreted?

No

Do TCRs ever go through affinity maturation?

No

What does a beta chain use to test its rearrangement?

Surrogate light chain

Is there ever allelic exclusion in the TCR?

Alpha chain never does allelic exclusion, beta chain does but is tightly regulated

Why does the alpha chain never do allelic exclusion?

The cell does not want to limit the chances that it succeeds

Where do positive and negative selection occur?

In the thymus

What does positive selection check?

Checks if TCR can successfully bind MHC/antigen complex

What is weird about delta chain recombination?

D box rearrangement allows for more diversity

What does CD2 bind?

LFA-3

What does CD5 bind?

CD72

What does LFA-1 bind?

ICAM-1

What does CD45R bind?

CD22 and CD45

What does the CD3 complex do?

Conveys signals received by the receptor to the interior of the cell.

What are the types of ITAMS?

Delta/epsilon, gamma/epsilon, z/z, z/e

What are the types of cells that myeloid progenitors make?

RBC, innate cells, Granulocytes

What are the types of cells that lymphoid progenitors make?

Lymphocytes

What type of cells support hematopoiesis?

Stromal macrophages

What will the cell become if Notch1R is expressed?

T cell

What will the cell become if Notch1R isn’t expressed?

B cell

What does a Notch1 signal tell the cell?

To go to the thymus

What does CD44 tell the cell?

To go to the thymus

How can we determine if a cell is a hematopoietic cell?

Express cKit and Sca1, Lin (-)

At what stage does the rearrangement race begin? (T Cells)

DN2

At what stage is the TCR successfully expressed on the surface?

DN4

At what stage do we need IL-2?

DN2-DN3

When does Apoptosis first turn on for T cell development?

Bone Marrow

What are the two signals for apoptosis to turn off?

IL-2 Signal, and complete TCR at start of DN4

When does apoptosis turn on again in T cell development?

During the middle of DN4

When does apoptosis turn off after DN4?

When cell passes positive selection in corex of thymus

What happens if a cell fails positive selection?

Death by neglect

What happens if a T cell fails negative selection?

Apoptosis turns on and cell dies

Why does negative selection sometimes happen simultaneously with positive selection?

If it binds to self antigen

What is negative selection?

Selection against T cells with TCRs that have high affinity for MHC/self peptides

When does negative selection usually occur?

During SP

Where does positive selection happen?

In cortex of the thymus

Where does negative selection occur?

In medulla of thymus

What is affinity?

Strength of a single bond

What is avidity?

Cumulative strength of multiple binding interactions

What is positive selection testing the TCR for?

Ability to recognize self MHC and have right amount of affinity

What is negative selection testing the TCR for?

Whether or not it binds too tight to self antigen

What makes positive and negative selection complicated?

Using self antigen for the process so TCR cannot bind too strong or weak.

What type of death occurs with positive selection?

Death by neglect (loss of survival signals)

What type of death occurs with negative selection?

Clonal deletion (Apoptosis)

What is the instructive model?

Whichever one binds first (CD4 or CD8) will be upregulated and the other downregulated

What is the stochastic model?

Randomly drop expression of one and express the other

What is the kinetic signaling model?

Drop CD8 and test CD4, if CD4 works --> Great! | If not: get IL-7 signal, upregulate CD8 and test

Why are Th cells predominant?

Due to the Kinetic Signaling model

Th1 cells release cytokines to kill

Virus

Th2 cells release cytokines to kill

Bacteria

Th17 cells release cytokines to kill

Fungi

What is the function of a Treg cell?

Downregulate immune response

What is the first signal in naive T cell activation?

TCR reading Ag on MHC

What is the second signal in T cell activation?

CD28 (T cell) binding B7 on B cell or CD80/86 on APC

What is the third signal in T cell activation?

IL2R (T cell) will bind IL-2 for devision

What happens after third signal in T cell activation?

Cell division

How long do effector T cells last?

3-10 days

Why do we not do point mutations on our TCR?

Point mutations could produce a self reactive T cell

How does the second signal in T cell activation reduce autoimmunity?

B7 and CD80/86 won’t express in high amounts without antigen present

What is at the bottom of CD8

P56lck

What does P56lck do?

Phosphorylates ITAMS of CD3 after recognizing MHC

What does Zap-70 do?

Binds to phosphorylated ITAMS and starts the signal cascade

What is the end resulf of the signal cascade?

Helps our cells change gene expression

Why are lipid rafts important?

Hold different receptor proteins in different areas so thatt T cells don’t get randomly activated

During what stage will we try another attempt at a successful heavy chain in B cell?

ProB

What are the protein chaing with ITAMs called for B cells?

IgAlpha/Beta

What is a T1 cell?

B cell that has not done negative selection

What is a T2 cell?

B cell that has surviced negative selection and not yet left bone marrow

What is a T3 cell?

B cell that doesn't respond to antigen, anergic, refuses activation since it was never negatively selected

What is the purpose of Src Kinases?

Phosphorylate ITAMs, get caught between cross linked antibodies

What is the purpose of BLNK?

Binds to antibodies to stabilize cross linking

What is the purpose of Syk?

Binds to phosphorylated ITAMS and starts cascade

What are the three Src Kinases you should know?

Blk, Fyn, Lyn

What does CD21 do?

Binds to C’3d opsonized antigen

What is next to CD21

CD19

What does CD21 do?

Phosphorylates CD19

What is the first step of CD21 signaling?

CD21 binds to C3d Ag

What is the second step in CD21 signaling?

TAPA1 activates cytoplasmic domain of CD21

What is the third step of CD21 signaling?

CD21 then phosphorylates CD19

What is the fourth step in CD21 signaling?

Phosphorylated CD19 begins a signal cascade to amplify the activation signals

What is the first signal in B cell activation?

Antigen Binding (Crosslink and CD19 cosignal)

What is the second signal in B cell activation?

CD40 binding CD40L (L on T cell)

What is the third signal in B cell activation?

Cytokines IL-2, 4, 5

What is an ITIM?

Immunoreceptor tyrosine inhibitory motif

Where are ITIMs found on B cell?

Bottom of CD22, binds CD22/CD45R

What is SHP-1?

Phosphorylated ITIMs activate it

What does SHP-1 do?

Removes phosphates from ITAMS so that the signal cascade cant start

What type of cells would not express CD22?

Effector cells

How do dendritic cells help with antigen presentation in the lymph nodes?

Hold Ag on surface without damaging it, bring Ag to lymph nodes, drop Ag in paracortex

When does the third signal happen?

On the way to a follicle

What happens inside the follicles