Lecture 6 - T cell response

Question 1

How is the antigen binding region of the TCR generated?

Answer 1

By rearranging gene segments of the alpha and beta chain. B chain locus has VDJ regions, A has just VJ regions

Question 2

In what order is the TCR rearranged?

Answer 2

B rearranged first then alpha

Question 3

How do antigen binding regions compare between Ig and TCR?

Answer 3

Both have three CDRs in Vh, Vl and Va Vb

Question 4

How do on and off rates compare between Ig and TCR?

Answer 4

Ig cells have higher affinity that changes over immune response. T cells have lower affinity which doesn’t change

Question 5

Where do T cell precursors originate then develop?

Answer 5

Bone marrow then develop in thymus

Question 6

How is the gamma-delta T cell receptor different from the alpha-beta?

Answer 6

Gamma-delta respond to lipid not peptide. Make up the majority of T cells in epithelium

Question 7

What accessory proteins are necessary for T cell binding?

Answer 7

CD4 or CD8 simultaneously with MHC

Question 8

What can double negative CD3/4/8 cells become?

Answer 8

gamma-delta CD3s, or if pre-TCR rearrangment is functional, double positive pre-TCRs

Question 9

What happens to most of the double positive TCRs?

Answer 9

95% apoptose, dye by neglect

Question 10

What happens to the double positive TCRs that do not die by neglect?

Answer 10

If they bind one CD just right they downregulate the other one and become single positive thymocytes which are exported to the periphery and mature as T cells. If they bind too strongly to either CD, they die by neg selection

Question 11

Which cells present peptide-MHC complexes to double positive thymocytes?

Answer 11

Thymic epithelial cells

Question 12

What are the two types of CD4 cells can CD4 T cells become?

Answer 12

Can become effector CD4 T cell (which can activate macrophages, B cells, other cells) or a memory CD4 T cell

Question 13

What are the two kinds of CD8 T cells can naive CD8 cells become?

Answer 13

Can become effector CD8/cytotoxic T lymph or memory CD8 T cell

Question 14

What is the role of CD3 in T cell activation?

Answer 14

CD3 chains are expressed along with the TCR and are responsible for initiating signal transduction/informing the cell that antigen has been bound

Question 15

What happens after CD4/CD8, TCR and CD3 are all activated?

Answer 15

Signal transduction which starts with the stimulation of Lck and ZAP-70 which eventually leads to the expression of transcription factors like NFAT, NF-kB and AP-1

Question 16

What happens if a T cell is only stimulated at the TCR by antigen/MHC?

Answer 16

Anergy/unresponsiveness

Question 17

What is the second signal necessary for T cell activation?

Answer 17

Co stimulation via binding of CD28 on T cell to B7 on APC

Question 18

What happens if a T cell only recieves co-stimulation?

Answer 18

Nothing, no effect.

Question 19

How is B7 upregulated on APCs?

Answer 19

Cytokines from other activated cells or by products of microorganisms stimulate pattern receptors on the APC

Question 20

What is the role of CD40:CD40L interactions in T cell activation?

Answer 20

Positive feedback loop between the APC and the T cell. T cells activated via MHC/ag and B7/CD28 express CD40L which binds to CD40 on APC which causes APC to upregulate B7 expresssion leading to more effective T cell stimulation

Question 21

What is the role of CTLA4 in T cell activation/suppression?

Answer 21

CTLA4 is a negative regulator expressed late in T cell activation. After CD28 co-stimulates it induces expression of CTLA4 which binds B7 with higher affinity and delivers inhibitory signals to activated T cells

Question 22

How does TCR stimulation lead to increased adhesion between T cells and APCs?

Answer 22

Promotes clustering and increased affinity of integrins

Question 23

What receptor/ligand is required for T cell proliferation?

Answer 23

IL 2 and its receptor.

Question 24

What are the two forms of IL-2 receptor and where/when are they expressed?

Answer 24

Low affinity two chains (B and G) and a high affinity with a third chain A. Low affinity expressed on naïve T cells (cant proliferate), High affinity expressed after TCR stimulation and can accept IL-2 made by activated T cell and neighboring cells

Question 25

How do cytokine receptors initiate biochemical signals?

Answer 25

Through dimerization and autophosphorylation of JAK which leads to activation of STATS that translocate to the nucleus to effect transcription

Question 26

Where do mature T cells circulate?

Answer 26

Through secondary lymphoid organs

Question 27

What happens if mature T cells have a strong TCR recongition in the secondary lymphoid organs?

Answer 27

Stimulated to proliferate and differentiate into effectors. Re-enter the circulation and migrate to site of infection where they bind to adhesion molecules in vascular endothelial cells so they can leave circulation for the infected tissue

Question 28

What do effector CTLs activated by antigen/MHC recognition no longer need? And what do they do?

Answer 28

No longer need costim. Signals delivered by TCR lead to release of granules towards the target cells

Question 29

What do CTL granules contain?

Answer 29

Perforin which forms pores in the target cell membranes. Granzymes which activate capsases (cleave target cell proteins) which enter through pores formed by porin.

Question 30

What happens if a virus is unable to infect a dendritic cell/other APCs per se?

Answer 30

Able to cross-present. Can present exogenous antigen to MHC class I restricted CD8 T cells using the exogenous processing machinery

Question 31

What does IFN-y secretion from CD4/8 and NK T cells do?

Answer 31

Actiate macrophages

Question 32

What does TGF-B secretion from CD4 regulator T cells and other cells do?

Answer 32

Inhibit T cell activation; cause differentiation of regulatory T cells

Question 33

What are the different subsets of CD4/helper T cell effectors and the cytokines that stimulate them?

Answer 33

Th1 via IFNy for intracellular pathogens. Th2 via IL-4 for parasitic worms (stimulate B cells to make IgE/G and via IL-5 recruit eosinophils). Th17 via IL-6 (plus TGFB) for extraceullar bacteria (can predispose to autoimmunity). aTreg via TGFB only for counter regulation

Question 34

What do TH1 cells secrete and stimulate (along with T-bet tx factor)?

Answer 34

IFNy Activate macrophages and stimulates B cells to make IgG for opsonization

Question 35

What do TH2 cells secrete and stimulate (along with GATA3 tx factor)?

Answer 35

Secrete IL4 which stimulates B cells to make IgG and IgE. Secrete IL4/13 to stimulate alternative macrophage to stimulate tissue repair/fibrosis. Secrete IL-5 to activate eosinophils

Question 36

What do Th17 cells secrete and stimulate (along with RORy tx factor)?

Answer 36

IL-17 which acts on cells to produce chemoattractants for neutrophils. IL-22 which improves barrier function of the epithelium (esp in intestinal tract)

Question 37

What happens if Th1 is overexpressed?

Answer 37

Inflammatory conditions

Question 38

What happens if Th2 is overexpressed?

Answer 38

Allergy, asthma

Question 39

What happens if Th17 is overexpressed?

Answer 39

Autoimmunity

Question 40

What happens if regulatory cells are overexpressed?

Answer 40

Diminished immune responses against tumors

Question 41

What happens to effector T cells that don’t die at the end of the immune response?

Answer 41

Become memory T ccells

Question 42

Where are memory cells found?

Answer 42

In circulation and in secondary lymphoid organs