CMB2004/L05 Lymphocyte Activation

Question 1

Where do naive T cells recirculate once they exit the thymus?

Answer 1

Via blood/lymphatics through secondary lymphoid tissue

Question 2

What triggers clonal proliferation and differentiation in naive T cells?

Answer 2

Contact with specific antigen and antigen-presenting cell

Question 3

Give the 2 types of T cells.

Answer 3

Cytotoxic effector T cells (CD8+) kill infected cells
Helper effector T cells (CD4+) secrete cytokines

Question 4

How do T cells get to the site of infection? (3)

Answer 4

Enter lymph node from blood via high endothelial venules (HEV)
Move into T cell area rich in dendritic cells and macrophages (APC)
APC present antigen and deliver other activation signals e.g., cytokines

Question 5

Where do inactivated T cells go?

Answer 5

Leave lymph nodes via cortical sinuses into lymphatics
Re-enter circulation to be recycled

Question 6

Describe cell adhesion molecules (CAM).

Answer 6

Molecules expressed on surface of T cells (chemokine receptors) expressed/released by other cells
Once close to other cells different molecular sets of CAMs mediate cell/cell interactions

Question 7

Describe T cell contact with APC. (5)

Answer 7

T cells contact APCs using CAMs
TCR scans APC peptide/MHC complexes
-no recognition -disengages
-recognition -signal from TCR complex
Increases affinity of CAM interactions
T cell divides
Progeny differentiate to effector cells & exit LN

Question 8

What is the role of LFA-1? (3)

Answer 8

Leukocyte function-associated antigen (integrin)
Interacts with ICAM-1 to help T cell binding to APC
Aids subsequent binding of T cell receptors signals LFA-1
Conformational change in LFA-1 increases affinity and prolongs cell-cell contact

Question 9

What is the role of ICAM-1?

Answer 9

Intercellular adhesion molecule
Interacts with LFA-1 to aid binding of T cell to APC

Question 10

Describe co-stimulation of T cells. (3)

Answer 10

Naive T cells receive a signal from TCR contacting MHC/peptide on APC (signal 1)
Involves CD3 (zeta) chain
Naive T cells need three signals for activation

Question 11

What is the function of co-stimulatory molecules released by professional APC?

Answer 11

Bind CD28 expressed by naive T cells and delivers signal 2 to the cell

Question 12

What is the function of cytokines released by APC?

Answer 12

Bind cytokine receptors now up-regulated on naive T cells which deliver signal 3

Question 13

Describe the 3 signals given to T cells by APCs for activation.

Answer 13

Activation
Survival
Differentiation

Question 14

What occurs once T cells are activated by the 3 required signals?

Answer 14

Proliferation
Expression of ICOS and CTLA-4

Question 15

What is the role of ICOS?

Answer 15

Related to CD28
Binds ICOSL on APC to induce cytokine secretion by T cells

Question 16

What is the role of CTLA-4?

Answer 16

Highly related to CD28
Shows stronger binding to B7.1/2 than CD28

Question 17

What is the effect of CTLA-4 binding to B7.1/2 on APC?

Answer 17

Delivers a negative signal to activated cell
Limits T cell response

Question 18

Describe the importance of CTLA-4.

Answer 18

Mutations of CTLA-4 associated with several autoimmune diseases e.g., Type 1 diabetes
Treatment of cancer patients with anti-CTLA-4 can enhance immune response to tumour

Question 19

How does co-stimulation expression vary? (2)

Answer 19

Constitutive on mature dendritic cells
Inducible on macrophages

Question 20

Activation of APC by pathogens causes co-stimulation expression providing which signal to T cells?

Answer 20

Signal 2 - survival

Question 21

Describe activation of APC.

Answer 21

Binding of pathogen-associated molecules activate APC
Leads to APC upregulation of MHC and co-stimulatory molecules
Ensures signal 2 to activate T cell-mediated response only occurs during infection

Question 22

What is the role of cytokines in co-stimulation?

Answer 22

Dictate the differentiation of activated CD4 cells into different subsets of effector cells

Question 23

Give 2 types of APC (express MHC class II molecules).

Answer 23

Dendritic cells (present Ag) crucial for activation of naive T cells
Macrophages and B cells present Ag to receive help from effector T cells

Question 24

Describe myeloid dendritic cells. (3)

Answer 24

Conventional DC (2,3)
Potent APC
Involved in activation of naive T cells
Bone marrow-derived
Macropinocytotic & phagocytotic
Induced to mature and migrate to lymph node following activation/maturation

Question 25

Describe plasmacytoid DC.

Answer 25

pDC, DC6 Important in viral infection Secrete several type I a and B interferons Express TLR 7 and 9 (sense viral antigens)

Question 26

Describe the series of events following activation of mature DC (2,3). (3)

Answer 26

Found in T cell areas of lymphoid tissues DC MHC class I & II loaded with peptides from pathogens in peripheral tissues Levels of co-stimulatory molecules very high Express high levels of adhesion molecules

Question 27

Describe how immature dendritic cells mature to prime naive T cells. (4)

Answer 27

Immature dendritic cells in peripheral tissues encounter pathogens and are activated by PAMPs TLR signalling induces CCR7 and enhances processing of pathogen-derived antigens CCR7 directs migration into lymphoid tissues and augments expression of co-stimulatory molecules and MHC molecules Mature dendritic cell in T cell zone primes naive T cells

Question 28

Define cross-presentation. (3)

Answer 28

Soem specialised DC (DC1) take up and process exogenous Ag and present it via MHC class I molecules Allows DC to activate naive CD8+ T cells Can then kill infected cells

Question 29

Give 3 functions of macrophages.

Answer 29

Scavengers/killers of pathogens Important APC for extracellular pathogens Highly phagocytic Express MHC class II and B7 Secrete inflammatory cytokines once activated

Question 30

Where are macrophages found?

Answer 30

Many tissues Peripheral sites Lymphoid tissues

Question 31

Give 1 function of B cells.

Answer 31

Internalise soluble Ag for processing and presentation by BCR Provide signal 2 to T cells by Ag binding to BCR

Question 32

Describe how B cells act as Ag-specific APC. (3)

Answer 32

Only antigen-specific B cell binds antigen Specific antigen internalised by receptor-mediated endocytosis high density of specific antigen fragments presented

Question 33

Describe the role of interleukin-2 (IL-2) in T cell survival.

Answer 33

Potent autocrine T cell growth factor IL-2 binding to IL-2R on activated T cells -> T cell proliferation Expands population of Ag-specific activated T cells Target of immunosuppressive drugs e.g., cyclosporin

Question 34

Describe the process by which IL-2 aids T cell survival.

Answer 34

Resting T cells express only moderate-affinity IL-2 receptor Activated T cells express high-affinity IL-2 receptor and secrete IL-2 Binding of IL-2 to its receptor signals T cell to enter cell cycle IL-2 induces T-cell proliferation

Question 35

What can T cells differentiate into following activation by APC? (2)

Answer 35

Effector T cells: CD8+ cells CD4+ cells types of effecter sub set generated by signal 3

Question 36

Which signal determines the effector sub-set of T cells?

Answer 36

Signal 3 from APC and environment/pathogen

Question 37

What is the function of effector T cells?

Answer 37

CD8+ cells acquire cytotoxic activity Kill cells expressing peptide/MHC class I complexes

Question 38

What is the function of CD4+ cells?

Answer 38

Secrete cytokines Effects on other cell types recognising peptide/MHC class II complexes

Question 39

Where do effector T cells migrate to? (2)

Answer 39

No longer enter lymph nodes Enter tissues via activated endothelia at sites of infection and inflammation

Question 40

Describe activation of CD8+ T cells.

Answer 40

Requires high levels of co-stimulator activity Can be activated directly by infected or cross-presenting APC May require help from CD4+ T cells