T cells and TCR

Question 1

the antigen binding domain of TCR consist of _____

Answer 1

3 CDR loops (complementarity-determining regions) in each alpha and beta chain

CDR1 interacts with MHC
CRD2 interacts with peptide
CRD3 determines specificity of TCR

Question 2

key difference in how antibodies and TCR binds antigens

Answer 2

TCR ONLY bind antigens + MHC complex (MHC peptide complex)

antibodies can directly bind native antigen

Question 3

what are the roles of the following T cell surface molecules:
a. CD28
b. CTLA-4
c. LFA-1
d. VLA-4

Answer 3

a. CD28: costimulation, binds APC (B7 on DC)
b. CTLA-4: inhibitory signaling, binds APC (B7 on DC)
c. LFA-1: adhesion, binds ICAM-1 on APC and endothelium
d. VLA-4: adhesion, binds VCAM-1 on endothelium

Question 4

what do LFA-1 and VLA-4 binds, respectively? both are expressed on T cell surface

Answer 4

LFA-1: binds ICAM-1 on APC and endothelium

VLA-4: binds VCAM-1 on endothelium

both important for adhesion

Question 5

which immune cells initiate most immune responses

Answer 5

dendritic cells (DC) - ONLY cells that can directly activate [naive] T cells

Question 6

how does cell surface expression change from an immature to a mature DC?

Answer 6

immature DC (surveillance) - express Fc receptors, mannose receptors

mature DC (activate T cells) - express B7, ICAM-1, IL-12 needed for T cells activation

Question 7

what 2 signals are needed for T cell activation (costimulation)

Answer 7

1. TCR binds antigen-HLA complex
2. CD28 on T cell binds B7 on DC

*** note that only naive T cells needs activation from DC and co-stimulation (once they are activated and mature they can function on their own)

Question 8

what would happen if a novel virus prevented DC cells from expressing B7?

Answer 8

for [naive] T cell activation, 2 signals are needed (costimulation):
1. TCR + antigen-HLA complex
2. CD28 (T cells) + B7 (DC)

so without B7 expression of DC, T cells could not be activated

Question 9

immunological anergy

Answer 9

immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen.

Question 10

after activation, T cell up-regulation expression of ____, which binds B7 on APC to shut down T cell response

Answer 10

CTLA-4: inhibitory signal transduction

**therapeutic potential for treating autoimmunity, as well as enhancing tumor immunity by blocking its function

Question 11

injecting soluble CTLA-4 and blocking CTLA-4 are both potential therapeutic treatments.

Explain why and how

Answer 11

CTLA-4 is a surface protein on T cells that binds B7 on APC to provide inhibitory signaling (shuts down T cell activity)

injecting soluble CTLA-4 can be therapeutic for treating autoimmunity

blocking CTLA-4 (with a monoclonal antibody) can enhance tumor immunity

Question 12

what are CD3-epsilon, gamma, and delta important for

Answer 12

CD3 is a T cell transmembrane molecule that is required for signal transduction by TCR complex

have longer intracelular tails than TCR, and contain ITAMs (immunoreceptor tyrosine based activation motif)

Question 13

what are the steps of early signaling in T cell activation (name the players involved)?

Answer 13

1. TCR complex + coreceptors cluster within lipid rafts upon antigen recognition
2. LCK (lymphocyte specific protein tyrosine kinase) phosphorylates ITAMs (immunoreceptor tyrosine-based activation motif) on CD3
3. ZAP-70 (zeta-chain associated protein) binds phosphorylated tyrosines, and phosphorylates LAT (linker for activation of T cells) adaptor protein

Question 14

fill in the blank regarding early signaling events in T cell activation:

1. TCR complex + coreceptors cluster within ____ upon antigen recognition
2. ____ phosphorylates ____ on CD3
3. _____ binds phosphorylated tyrosines, and phosphorylates _____adaptor protein

Answer 14

1. TCR complex + coreceptors cluster within lipid rafts upon antigen recognition
2. LCK (lymphocyte specific protein tyrosine kinase) phosphorylates ITAMs (immunoreceptor tyrosine-based activation motif) on CD3
3. ZAP-70 (zeta-chain associated protein) binds phosphorylated tyrosines, and phosphorylates LAT (linker for activation of T cells) adaptor protein

Question 15

function of T helper 1 vs 2 cells

Answer 15

Th1: activate macrophages via IFNy (gamma)

Th2: activate B cells via IL-4/5/13

**remember that T helper cells are CD4 T cells, so they recognize MHC II (exogenous) on APC

Question 16

for each of these, state what cytokines they produce, what immune reaction they cause, and what host defense + roles in disease they have:
a. Th1
b. Th2
c. Th17

Answer 16

a. Th1: produce IFNy —> macrophage activation, IgG production. Intracellular microbe defense, involved in autoimmunity and tissue damage associated with chronic infection

b. Th2: produce IL-4/5/13 —> B cell, mast cell, eosinophil activation, IgE production. Parasite defense, involved in allergic reaction

c. Th17: produce IL-17A/F, IL-22 —> neutrophil and monocyte activation. Extracellular bacteria and fungi defense, involved in organ-specific autoimmunity

Question 17

what type of T helper does this describe?
- produce IFNy
- cause IgG production
- defense against intracelular microbes

Answer 17

Th1:
- produce IFNy —> activate macrophages
- cause IgG production
- defense against intracelular microbes
- involved in autoimmune diseases, tissue damage associated with chronic infection

Question 18

what type of T helper does this describe?
- produce IL-4, IL-5, IL-13
- cause IgE production
- parasitic defense
- role in allergic diseases

Answer 18

Th2:
- produce IL-4, IL-5, IL-13
- activate B cells, mast cell, eosinophilic
-cause IgE production —> parasitic defense and role in allergies

Question 19

what type of T helper does this describe?
- produces Il-17A, IL-17F, IL-22
- causes neutrophilic and monocytic inflammation
- defense against fungi
- role in organ-specific autoimmunity

Answer 19

Th17:
- produces IL-17A, IL-17F, IL-22
- causes neutrophilic and monocytic inflammation
- defense against fungi (and extracellular bacteria)
- role in organ-specific autoimmunity

Th17 produces IL-17

Question 20

key role of Tregs

Answer 20

regulatory T cells maintain tolerance - inhibition of T cell activation and T cell effector function

Question 21

how does SIV (simian immunodeficiency virus)/ HIV evade the immune system?

Answer 21

SIV mutates amino acids necessary for binding to MHC I, thereby evading CD8 T cells

Question 22

what are the 2 phases of selection of thymocytes in T cell development?

Answer 22

1. positive selection: chooses T cells with useful TCRs (those that bind/interact with self-HLA)
2. negative selection: eliminate T cells with self-reactive TCRs (central tolerance)

*remember that central tolerance (removal of self-reactive clones) occurs in thymus (T cells) and bone marrow (B cells)

Question 23

T cell maturation increases in a gradient in what direction in the thymus?

Answer 23

from cortex —> medulla, increasing T cell maturation

cortex stromal cells involved in positive selection
medulla stromal cells involved in negative selection

Question 24

where do T cell subsets develop

Answer 24

in the thymus - differentiation and positive/negative selection

can become CD4+, CD8+, Treg, NK cells, etc

Question 25

how does the CD4+ T cell repertoire change with age

Answer 25

thymic function decreases with age

basically, diversity of T cells is established earlier in life

with age, the repertoire of naive T cells becomes established

later in life, contraction occurs - less diversity

Question 26

following a bone marrow transplant, the immune cells will have the genotype of the _____, while the epithelial/stromal cells will have the genotype of the _____

Answer 26

hematopoietic cells are killed by chemotherapy or radiation, but not epithelial/stromal cells

so immune cells will have genotype of donor, while epithelial/stromal cells will have genotype of host

Question 27

T/F: in T cell development, cells begin double negative (CD4-/CD8-) to double positive (CD4+/CD8+) to single positive (CD4+ or CD8+)

Answer 27

TRUE

Question 28

in the predominant pathway of processing and presentation of viral antigens to CTL:
a. antigen is cleaved into peptides in an endosomal or lysosomal compartment
b. antigen is synthesized in the cytosol of an infected cell
c. peptides derived from the antigen are transported into lysosomes

Answer 28

b. antigen is synthesized in the cytosol of an infected cell

viruses use host machinery to manufacture proteins (antigens)

these are degraded by proteosome