CMB2004/L05 Lymphocyte Activation Flashcards
Where do naive T cells recirculate once they exit the thymus?
Via blood/lymphatics through secondary lymphoid tissue
What triggers clonal proliferation and differentiation in naive T cells?
Contact with specific antigen and antigen-presenting cell
Give the 2 types of T cells.
Cytotoxic effector T cells (CD8+) kill infected cells
Helper effector T cells (CD4+) secrete cytokines
How do T cells get to the site of infection? (3)
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
Where do inactivated T cells go?
Leave lymph nodes via cortical sinuses into lymphatics
Re-enter circulation to be recycled
Describe cell adhesion molecules (CAM).
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
Describe T cell contact with APC. (5)
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
What is the role of LFA-1? (3)
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
What is the role of ICAM-1?
Intercellular adhesion molecule
Interacts with LFA-1 to aid binding of T cell to APC
Describe co-stimulation of T cells. (3)
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
What is the function of co-stimulatory molecules released by professional APC?
Bind CD28 expressed by naive T cells and delivers signal 2 to the cell
What is the function of cytokines released by APC?
Bind cytokine receptors now up-regulated on naive T cells which deliver signal 3
Describe the 3 signals given to T cells by APCs for activation.
Activation
Survival
Differentiation
What occurs once T cells are activated by the 3 required signals?
Proliferation
Expression of ICOS and CTLA-4
What is the role of ICOS?
Related to CD28
Binds ICOSL on APC to induce cytokine secretion by T cells
What is the role of CTLA-4?
Highly related to CD28
Shows stronger binding to B7.1/2 than CD28
What is the effect of CTLA-4 binding to B7.1/2 on APC?
Delivers a negative signal to activated cell
Limits T cell response
Describe the importance of CTLA-4.
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
How does co-stimulation expression vary? (2)
Constitutive on mature dendritic cells
Inducible on macrophages
Activation of APC by pathogens causes co-stimulation expression providing which signal to T cells?
Signal 2 - survival
Describe activation of APC.
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
What is the role of cytokines in co-stimulation?
Dictate the differentiation of activated CD4 cells into different subsets of effector cells
Give 2 types of APC (express MHC class II molecules).
Dendritic cells (present Ag) crucial for activation of naive T cells
Macrophages and B cells present Ag to receive help from effector T cells
Describe myeloid dendritic cells. (3)
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
Describe plasmacytoid DC.
pDC, DC6
Important in viral infection
Secrete several type I a and B interferons
Express TLR 7 and 9 (sense viral antigens)
Describe the series of events following activation of mature DC (2,3). (3)
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
Describe how immature dendritic cells mature to prime naive T cells. (4)
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
Define cross-presentation. (3)
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
Give 3 functions of macrophages.
Scavengers/killers of pathogens
Important APC for extracellular pathogens
Highly phagocytic
Express MHC class II and B7
Secrete inflammatory cytokines once activated
Where are macrophages found?
Many tissues
Peripheral sites
Lymphoid tissues
Give 1 function of B cells.
Internalise soluble Ag for processing and presentation by BCR
Provide signal 2 to T cells by Ag binding to BCR
Describe how B cells act as Ag-specific APC. (3)
Only antigen-specific B cell binds antigen
Specific antigen internalised by receptor-mediated endocytosis
high density of specific antigen fragments presented
Describe the role of interleukin-2 (IL-2) in T cell survival.
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
Describe the process by which IL-2 aids T cell survival.
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
What can T cells differentiate into following activation by APC? (2)
Effector T cells
CD4+ cells
Which signal determines the effector sub-set of T cells?
Signal 3 from APC and environment/pathogen
What is the function of effector T cells?
CD8+ cells acquire cytotoxic activity
Kill cells expressing peptide/MHC class I complexes
What is the function of CD4+ cells?
Secrete cytokines
Effects on other cell types recognising peptide/MHC class II complexes
Where do effector T cells migrate to? (2)
No longer enter lymph nodes
Enter tissues via activated endothelia at sites of infection and inflammation
Describe activation of CD8+ T cells.
Requires high levels of co-stimulator activity
Can be activated directly by infected or cross-presenting APC
May require help from CD4+ T cells
