Activation of B and T cells by Antigen Flashcards
Priming in T cells?
- when a naive T cell encounters its specific antigen and is stimulated to differentiate into an effector T cell
- first step in any adaptive immune response
is the adaptive immune response initiated at the site of infection?
no, helper T cells and naive cells come into contact with pathogen and then T cells differentiate into effector cells in secondary lymph tissue
Where does activation of helper T cells generally occur?
-secondary lymph tissue
Where does activation of helper T cells occur for antigens in the skin and other peripheral tissues?
regional lymph nodes
Where does activation of helper T cells occur for antigens that are blood borne?
spleen
Where does activation of helper T cells occur for antigens in the respiratory mucosa?
tonsils and bronchial associated lymph tissue
Where does activation of helper T cells occur for antigens in the gastrointestinal system?
- peyers patch
- GALT
- appendix
How does the antigen get to secondary lymphoid tissue?
dendritic cells and macrophages:
- act as sentinels for infection in tissue
- upon infection, both cells uptake pathogens
- can process and present antigen
- macrophages have a range of function
What is the function of dendritic cells?
trigger T cell responses
Difference in dendritic cells vs macrophages?
Dendritic:
- migratory
- carry antigen load from site of infection to nearest secondary lymph tissue
Macrophage:
- resident in tissues, do not migrate
- macrophages resident in lymph tissue can process and present antigen that is carried passively in lymph form infected tissue
Dendritic cells reach their locations because activation induces expression of what?
CCR7, the receptor for chemokine CCL21
Once dendritic cells enter lymph nodes, where do they settle?
T cell areas -in the center
What is the anatomy of an immune response (general process)?
- naive T cells brought to lymph nodes via the blood
- they bind to endothelial cells in thin walled high endothelial venues (HEV)
- squeeze through vessel wall
- enter cortical region of lymph node
- pass through tissue, examine antigen presenting cells (dendritic and macrophages)
- if they see antigen, they active, proliferate, and differentiate into effector cells
- if they don’t see antigen, they recirculate out from efferent lymph
What is the detailed process about how lymphocytes leave the blood stream and enter secondary lymph tissue?
- circulating lymphocyte enters the HEV
- L-selectin binds with CD34 and GlyCam-1 on the endothelium which allows rolling interaction
- LFA-1 is activated by chemokines (CCL21 binds to chemokine receptor CCR7)
- activated LFA-1 binds to ICAM-1 and ICAM-2 (Ig superfamily)
- diapedesis- lymphocyte leaves blood and enters lymph node
What enhances the homing of T cells to draining lymph nodes?
sites of acute inflammation:
- egress via efferent lymphatics transiently reduced
- due to cytosine produced as part of the innate immune response (IFNs)
Once inside the lymph tissue, what are the initial adhesive interactions between T cell and dendritic cell?
- T cells initially bind dendritic cell though low affinity LFA1: ICAM1 interactions
- subsequent binding of T cell receptors (TCR) to MHC class 2 in CD4+ cells, signals LFA1
- conformational change in LFA1 increases affinity and prolongs cell to cell contact
What is the first signal that antigen presenting cells deliver to naive T cells?
- engagement of the TCR
- signals activation of helper T cells
How does the engagement of TCR induce activation of T cells? process?
- V regions of TCR engage the MHC 2 complex containing the peptide
- CD4 interacts with MHC 2
- intracellular signaling by CD3 which activates protein kinase C and GTP binding proteins
- activation of Helper T cells
- changes in gene expression in cytokines, growth factors, cytokine receptors, and other activation proteins
What is the 2nd signal that antigen presenting cells deliver to naive T cells (now activated)?
co stimulation CD28 and B7-1/B7-2 interaction
Why is the 2nd signal important? what interacts? what happens in the absence of this interaction?
- ligation of just TCR is insufficient for activation -survival
- B7-1 (CD80) and B7-2 (CD86) interact with CD28 -costimulatory
- in its absence, leads to inactivation of T cell, anergy, tolerance
What is used as a costimulatory blockade?
CTLA-4-Ig associates with B7 (cannot associate CD28)
What makes the IL-2 receptor have high affinity for IL-2?
activation induced expression of CD25 (IL-2Ra)
Functions of IL-2?
- stimulates survival, proliferation, and differentiation of T lymphocytes (autocrine growth factor)
- maintains functional regulatory T cells and thus controls immune responses
What is the most important protein involved in CD4+ effector function?
CD40L
-binds to CD40 on macrophages, dendritic cells and B cells to secrete cytokines that differentiate and proliferate T cells (Th1, Th2, Th17)
What does the activation of CD40 do for B cells? macrophages?
B- promotes proliferation, antibody secretion, class switching (humoral)
macro- activation, killing of phagocytksed microbes (cell mediated)
Th1? Th2? Th17?
1, 17-inflammation
2- humoral
What is signal 3 in T cells?
- differentiation
- cytokines drive this step
What cytokines cause differentiation of CD4+ cells into TH17?
TGF-beta
IL-6
What cytokines cause differentiation of CD4+ cells into TH1?
IL-12
IFN-gamma
What cytokines cause differentiation of CD4+ cells into TH2?
IL-4
What cytokines do TH1 cells produce? functions?
IFN-gamma:
- macrophage activation
- IgG production
- intracellular microbes- host defense
- autoimmune disease
- tissue damage associated with chronic inflammation
What cytokines do TH2 cells produce? functions?
IL-4, IL-5, IL-13
- mast cell, eosinophil activation
- IgE production
- helminthic parasites- host defense
- allergies
What cytokines do TH17 cells produce? functions?
IL-17, IL-22
- neutrophilic, monocytic inflammation
- extracellular bacteria, fungi- host defense
- autoimmune inflammatory diseases
What is the role of B cells in the immune response?
Production of antibodies:
-clearance of organisms present in extracellular space like free virus that replicate inside cells and bacteria
Not toxic by themselves:
- neutralization
- opsonization (phagocytosis), promotes complement
- targets for complement mediated destruction
Primary response vs secondary response in antibodies?
primary:
- peak response smaller, slower
- usually IgM
- lower affinity
- induced by immunogens
secondary:
- larger peak, faster
- increases in IgG
- higher affinity
- unduced by protein antigens
What type of antigens do B cells see? how do they recognize them?
- see linear or conformational
- recognized by surface immunoglobulin
How does surface immunoglobulin in B cells recognize antigens?
Induces intracellular signal events:
- BCR
- Tyrosine kinase
- complement receptor
- Toll like receptor
How are soluble (native) antigen delivered to B cells? small and large?
- small antigens delivered to B cells in follicles through afferent lymphatics and via conduits
- large are delivered by sub scapular sinus macrophages or by dendritic cells in the medulla
What are follicular dendritic cells?
- no show MHC class 2
- B cells encounter antigens here
What cell responses does antigen induced cross linking of the B cell antigen receptor cause?
- production of proteins that promote survival and proliferation
- expression of costimulators and cytokine receptors that promote interactions with helper T cells
- responsiveness to helper T cells
- migration of cells toward T cells as a result of expression of CCR7
What is the sequence of events in humoral immune response?
- recognition of antigens by B cells and CD4+ T cells
- activated lymphocytes migrate toward one another and interact, resulting in B cell proliferation and differentiation
- restimulation of B cells by helper T cells in extra follicular sites leads to early isotope switching and short lived plasma cell generation, activation of T cells by B cells results in the introduction of follicular helper T cells
- late events occur in germinal centers and include somatic mutation and the selection of high affinity cells (affinity maturation)
- additional isotype switching
- memory B cell generation
- generation of long lived plasma cell
Explain antigen presentation on B cells to helper T cells?
- antigen activates B cells
- induce expression of MHC class 2
- becomes plasma cell
- some antigen goes through receptor mediated endocytosis, is internalized and processed
- antigen fit into MHC class 2 peptide complex
- looking for activated CD4+ T cell
How does the T cell interact with the B cell?
TCR and CD40L on the activated T cell interact with MHC class 2 and CD40 on on the B cell
What is the interaction of CD40 and CD40L important for in B cells?
differentiation and class switching
What does the dark zones contain in germinal centers of lymph? what happens here?
- contain activated proliferating B cells
- extensive isotype switching
- somatic hypermutation of Ig V genes
- migrate to light zones
What are light zones rich in at germinal centers? what B cells are selected to survive?
- rich in follicular dendritic cells (displaying antigen) and T FH cells
- B cells with highest affinity Ig receptors are selected to survive
- differentiate into antibody secreting cells and memory B cells
What cells leave germinal centers? where do they go?
- antibody secreting cells leave
- reside in bone marrow as long lived cells
- memory B cells enter recirculating lymphocyte pool
Describe the overall process at germinal centers?
- B cells proliferate in dark zones
- move to light zones where B cells with high affinity for Ig are selected to survive, differentiate into antibody secreting cells or memory B cells
- leave lymph and go to bone marrow or are recirculated
How do the helper T cells migrate to the germinal center to activate B cells?
- follicular helper T cells express CXCR5 (chemokine receptor)
- follicular dendritic cells are producing relevant chemokine (ICOS-L, ICOS) to bring it close to the germinal center
- enter B cell zone once activated by B cell
lower number = ____ affinity.
greater
somatic mutations in Ig V genes leads to what?
greater affinity to antigen
T cell CD40L engages ____ on an ______.
CD40 on activated B cell
If cytokines produced by interaction of B cell with T cell are IL-4, what class switching do we get?
IgE
IgG4
If cytokines produced by interaction of B cell with T cell are IFN-gamma, what class switching do we get?
IgG subclasses (IgG1, IgG3)
What are T independent antigens? how? what are often TI antigens?
- some antigens stimulate B cells without T cells antigen has repeating subunits:
- causes extensive BCR cross linking
- pnuemococcal, salmonella antigen can directly stimulate B cell at high concentrations:
- binds to B cell via surface marker distinct from surface Ig (ex. bacterial polyliposaccharide) polysaccharides are often TI antigens:
- can be made T-dependent if conjugated to a protein
- implications for vaccine, not ideal
What do TI antigens cause? Because no T cell help, what doesn’t happen?
- cause proliferation and IgM secretion in absence of T cell help
- No T cell help:
- no class switching
- no memory
