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Activation of B and T cells by Antigen Flashcards

1
Q

Priming in T cells?

A
  • 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
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2
Q

is the adaptive immune response initiated at the site of infection?

A

no, helper T cells and naive cells come into contact with pathogen and then T cells differentiate into effector cells in secondary lymph tissue

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3
Q

Where does activation of helper T cells generally occur?

A

-secondary lymph tissue

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4
Q

Where does activation of helper T cells occur for antigens in the skin and other peripheral tissues?

A

regional lymph nodes

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5
Q

Where does activation of helper T cells occur for antigens that are blood borne?

A

spleen

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6
Q

Where does activation of helper T cells occur for antigens in the respiratory mucosa?

A

tonsils and bronchial associated lymph tissue

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7
Q

Where does activation of helper T cells occur for antigens in the gastrointestinal system?

A
  • peyers patch
  • GALT
  • appendix
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8
Q

How does the antigen get to secondary lymphoid tissue?

A

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
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9
Q

What is the function of dendritic cells?

A

trigger T cell responses

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10
Q

Difference in dendritic cells vs macrophages?

A

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
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11
Q

Dendritic cells reach their locations because activation induces expression of what?

A

CCR7, the receptor for chemokine CCL21

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12
Q

Once dendritic cells enter lymph nodes, where do they settle?

A

T cell areas -in the center

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13
Q

What is the anatomy of an immune response (general process)?

A
  • 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
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14
Q

What is the detailed process about how lymphocytes leave the blood stream and enter secondary lymph tissue?

A
  1. circulating lymphocyte enters the HEV
  2. L-selectin binds with CD34 and GlyCam-1 on the endothelium which allows rolling interaction
  3. LFA-1 is activated by chemokines (CCL21 binds to chemokine receptor CCR7)
  4. activated LFA-1 binds to ICAM-1 and ICAM-2 (Ig superfamily)
  5. diapedesis- lymphocyte leaves blood and enters lymph node
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15
Q

What enhances the homing of T cells to draining lymph nodes?

A

sites of acute inflammation:

  • egress via efferent lymphatics transiently reduced
  • due to cytosine produced as part of the innate immune response (IFNs)
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16
Q

Once inside the lymph tissue, what are the initial adhesive interactions between T cell and dendritic cell?

A
  1. T cells initially bind dendritic cell though low affinity LFA1: ICAM1 interactions
  2. subsequent binding of T cell receptors (TCR) to MHC class 2 in CD4+ cells, signals LFA1
  3. conformational change in LFA1 increases affinity and prolongs cell to cell contact
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17
Q

What is the first signal that antigen presenting cells deliver to naive T cells?

A
  1. engagement of the TCR
  2. signals activation of helper T cells
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18
Q

How does the engagement of TCR induce activation of T cells? process?

A
  1. V regions of TCR engage the MHC 2 complex containing the peptide
  2. CD4 interacts with MHC 2
  3. intracellular signaling by CD3 which activates protein kinase C and GTP binding proteins
  4. activation of Helper T cells
  5. changes in gene expression in cytokines, growth factors, cytokine receptors, and other activation proteins
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19
Q

What is the 2nd signal that antigen presenting cells deliver to naive T cells (now activated)?

A

co stimulation CD28 and B7-1/B7-2 interaction

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20
Q

Why is the 2nd signal important? what interacts? what happens in the absence of this interaction?

A
  • 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
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21
Q

What is used as a costimulatory blockade?

A

CTLA-4-Ig associates with B7 (cannot associate CD28)

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22
Q

What makes the IL-2 receptor have high affinity for IL-2?

A

activation induced expression of CD25 (IL-2Ra)

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23
Q

Functions of IL-2?

A
  • stimulates survival, proliferation, and differentiation of T lymphocytes (autocrine growth factor)
  • maintains functional regulatory T cells and thus controls immune responses
24
Q

What is the most important protein involved in CD4+ effector function?

A

CD40L

-binds to CD40 on macrophages, dendritic cells and B cells to secrete cytokines that differentiate and proliferate T cells (Th1, Th2, Th17)

25
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)
26
Th1? Th2? Th17?
1, 17-inflammation 2- humoral
27
What is signal 3 in T cells?
- differentiation - cytokines drive this step
28
What cytokines cause differentiation of CD4+ cells into TH17?
TGF-beta IL-6
29
What cytokines cause differentiation of CD4+ cells into TH1?
IL-12 IFN-gamma
30
What cytokines cause differentiation of CD4+ cells into TH2?
IL-4
31
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
32
What cytokines do TH2 cells produce? functions?
IL-4, IL-5, IL-13 - mast cell, eosinophil activation - IgE production - helminthic parasites- host defense - allergies
33
What cytokines do TH17 cells produce? functions?
IL-17, IL-22 - neutrophilic, monocytic inflammation - extracellular bacteria, fungi- host defense - autoimmune inflammatory diseases
34
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
35
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
36
What type of antigens do B cells see? how do they recognize them?
- see linear or conformational - recognized by surface immunoglobulin
37
How does surface immunoglobulin in B cells recognize antigens?
Induces intracellular signal events: - BCR - Tyrosine kinase - complement receptor - Toll like receptor
38
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
39
What are follicular dendritic cells?
- no show MHC class 2 - B cells encounter antigens here
40
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
41
What is the sequence of events in humoral immune response?
1. recognition of antigens by B cells and CD4+ T cells 2. activated lymphocytes migrate toward one another and interact, resulting in B cell proliferation and differentiation 3. 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 4. 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
42
Explain antigen presentation on B cells to helper T cells?
1. antigen activates B cells 2. induce expression of MHC class 2 3. becomes plasma cell 4. some antigen goes through receptor mediated endocytosis, is internalized and processed 5. antigen fit into MHC class 2 peptide complex 6. looking for activated CD4+ T cell
43
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
44
What is the interaction of CD40 and CD40L important for in B cells?
differentiation and class switching
45
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
46
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
47
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
48
Describe the overall process at germinal centers?
1. B cells proliferate in dark zones 2. 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 3. leave lymph and go to bone marrow or are recirculated
49
How do the helper T cells migrate to the germinal center to activate B cells?
1. follicular helper T cells express CXCR5 (chemokine receptor) 2. follicular dendritic cells are producing relevant chemokine (ICOS-L, ICOS) to bring it close to the germinal center 3. enter B cell zone once activated by B cell
50
lower number = ____ affinity.
greater
51
somatic mutations in Ig V genes leads to what?
greater affinity to antigen
52
T cell CD40L engages ____ on an \_\_\_\_\_\_.
CD40 on activated B cell
53
If cytokines produced by interaction of B cell with T cell are IL-4, what class switching do we get?
IgE IgG4
54
If cytokines produced by interaction of B cell with T cell are IFN-gamma, what class switching do we get?
IgG subclasses (IgG1, IgG3)
55
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
56
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

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