3. Initiation of Immune Response Flashcards
1
Q
What are the lymphoid organs?
A
- Primary lymphoid organs > where immune cells develop
> bone marrow/ thymus - Secondary lymphoid organs > where immune response initiated
> lymph nodes/ spleen/ MALT
2
Q
How does the bone marrow support hematopoiesis?
A
- stem cell niche in bone marrow supports hematopoiesis
> perivascular niche- lines blood vessels
> endosteal niche > lines the bone
3
Q
How do B/T cells develop in the bone marrow?
A
- B cell progenitors in endosteal niche in association with osteoblasts
- more mature B cells in central sinuses of bone marrow
> exit to complete their maturation in the spleen - T cell progenitors exit at very immature stage > develop in thymus
4
Q
How do T cells complete their maturation in the thymus?
A
- T cell precursors enter thymus in blood vessels at corticomedullary junction > DN thymocytes
- DN cells travel to subcapsular cortex, where they proliferate
- travel to cortex > express mature TCRs/ become DP (upregulate CD4/CD8 markers)
- DP cells tested for ability of TCRs to bind MHC-peptide complexes on cTECs > positive/ negative selection
- positively selected DP thymocytes mature > become SP (lose a marker)/ migrate to thymic medulla where encounter mTECs
> mTECs express proteins otherwise exclusively found in other organs > negatively select autoreactive T cells not deleted in cortex - mature SP cells exit thymus as entered via corticomedullary junction
5
Q
What is positive/ negative selection?
A
- DP thymocytes in thymic cortex interact with cTECs
> cortical thymic epithelial cells - DP cells tested for ability of TCRs to bind MHC-peptide complexes on cTECs
> negative selection- bind too high affinity induced to die
> positive selection- bind with intermediate affinity survive - SP thymocytes in thymic medulla interact with mTECs
> medullary thymic epithelial cells - mTECs express proteins otherwise found in other organs > negatively select autoreactive T cells not deleted in cortex
6
Q
What are the goals of positive/ negative selection?
A
- Positive selection > selects for thymocytes with receptors capable of binding self-MHC molecules with low affinity > MHC restriction
- Negative selection > selects against thymocytes with receptors with high affinity for self-MHC/ self-peptide complexes > self-tolerance
7
Q
What are 3 common features of secondary lymphoid organs?
A
- have anatomically distinct regions of T/ B cell activity
- develop lymphoid follicles (for selection of B cells > affinity maturation)
- connected via blood/ lymphatic circulatory systems
8
Q
What is the first lymphoid structure to encounter antigens that enter tissue spaces?
A
Lymph nodes
9
Q
What are the divisions of lymph nodes?
A
- Cortex > lymphocytes (mostly B cells)/ macrophages/ follicular DCs
- Paracortex > T cells/ DCs
- Medulla > sparsely populated lymphoid lineage cells/ plasma cells
10
Q
How does an antigen enter the lymph nodes?
A
- enters cortex via afferent lymphatic vessels
- either in particulate form or presented on surface of migrating APCs
- particulate antigen can be presented on surface of resident DCs in paracortex
11
Q
How do T cells enter the lymph nodes/ encounter antigens?
A
- T cells enter cortex through HEVs
- browse MHC-peptide complexes on DCs in paracortex
- if bind to MHC-peptide complex > proliferate/ differentiate into effector cells
- if do not bind to MHC-peptide complex > exit lymph node via efferent lymphatics in medulla (not via blood)
12
Q
What helps T cells browse MHC-peptide complexes on APCs?
A
- APCs wrap themselves around long processes of FRCs
- FRCs (fibroblastic reticular cells) in paracortex guide T cell movements
13
Q
How do B cells enter lymph nodes/ what happens to them?
A
- B cells enter cortex via HEVs like T cells
- migrate to follicles > binds/ processes antigen/ presents on surface
> binding to antigen partially activates B cells
> FRCs may initially guide B cells but ultimately depends on FDCs (follicular dendritic cells) in follicles - B cell moves to paracortex > bind to Th cell that recognizes its MHC-peptide complex
> upon binding to T cell, B cell becomes fully activated
> some activated B cells differentiate into plasma cells
> some re-enter follicle to establish a germinal center
14
Q
What are the distinct stages of lymphocyte entry into lymph nodes from the blood?
A
- Rolling- interactions of selectins on T cells/ vascular addressins on HEV > rolling of T cells along surface of HEV
- Activation- chemokines on HEV activate receptors on T cells
- Adhesion- ↑ affinity of integrins on T cells for adhesion molecule on HEV > strong adhesion
- Diapedesis- T cells follow gradients of chemokines to pass through HEV wall
15
Q
What cells can undergo the multi-step adhesion cascade to home in the lymph nodes?
A
- naive B cells/ naive T cells
- central memory T cells
- NOT effector T cells
16
Q
What happens when naive T cells encounter antigen in lymph nodes?
A
- T cell becomes activated/ starts proliferating (clonal expansion)
- loses ability to exit the lymph node (trapping)
- activated T cells differentiate > effector cells
- antigen-specific effector T cells regain ability to exit LN > circulation
17
Q
What is trapping of T cells in the lymph node?
A
- trapping/ activation of antigen-specific naive T cells in lymph nodes
> detained transiently in lymph node where they become activated - within 48 hours, all antigen-specific naive T cells in body can be trapped in lymph node
18
Q
How are transient adhesive interactions between T cells/ APCs stabilized?
A
- T cells initially bind APCs through low-affinity LFA-1: ICAM-1 interaction
- binding of TCR receptor signals LFA-1 conformational change
> ↑ affinity/ prolongs cell-cell contact
19
Q
What 3 signals do APCs deliver to naive T cells?
> activation of naive T cells by APCs
A
- Activation- foreign peptide-self MHC/ TCR + co-receptor (CD4/ CD8)
> partial T cell activation - Survival/ Costimulatory signal- CD28 (T cell)/ B7 (APC)
> effective T cell activation (↑ survival/ proliferation) - Differentiation- cytokines from APC act on T cells
> T cell differentiation
20
Q
How do T cells respond to cytokine IL-2?
A
- resting T cells express only moderate affinity IL-2 receptor
- activated T cells express high affinity IL-2 receptor/ secrete IL-2
- binding of IL-2 to its receptor promotes accelerated cell cycling
- IL-2 modulates T cell differentiation/ enhances proliferation
21
Q
What regulates the proliferative phase of the T-cell response?
A
- CTLA-4 binds B7 (on APCs) with ↑ affinity than CD28
> delivers inhibitory signals to activated T cells - naive T cells express CD28 > costimulatory signal on binding B7 > survival/ proliferation of T cells
- activated T cells express CTLA-4 > binds most/ all B7 > limits/ regulates proliferative phase of T cells
22
Q
What influences helper T cell subset differentiation?
A
- differential signalling through dendritic cell PRRs
> different cytokines produced - cytokines interact with receptors on naive CD4+ T cells
> different cytokines turn on certain genes determining cells functional phenotype
23
Q
What are the differences between Th1 vs Th2 responses?
A
- Th1 > intracellular pathogens inducing cell-mediated immunity
(viruses/ bacteria/ fungi) - Th2 > extracellular pathogens inducing humoral immunity (particularly extracellular parasites ex-worms)
24
Q
What are 2 diseases associated with imbalances in Th1/Th2 responses?
A
- Lepromatous leprosy (Th2 > Th1)
> humoral immune responses dominate - Tuberculoid leprosy (Th1 > Th2)
> cell-mediated immune responses dominate
25
Q
What are the steps in the maturation/ selection of B cells?
A
- immature B cells have IgM receptors
> each B cells has receptors with only 1 antigen specificity - any B cell with receptors specific for self-antigens are deleted
- B cells without self-reactive receptors mature > express both IgM/ IgD
- clonal selection of B cells with receptor specific for antigen
- clonal expansion > effector B cells (plasma cells)/ memory B cells
> plasma cells secrete antibodies reactive with activating antigen
26
Q
What are the types of B cell responses?
A
- type of B cell response determined by antigen type
- T-dependent > TD antigens are protein antigens
- T-independent. > TI-1 antigens/ TI-2 antigens
27
Q
What is the T-dependent B cell response?
A
- generated upon recognition of protein antigens (TD antigens)
- requires participation of T helper cells
- mediated by B2 B cells (B cells)
28
Q
What 3 signals are required for the T-dependent B cell response?
A
- binding of multivalent antigen to BCR (Ig receptors)
- binding of Th cell/ B cell through TCR/ MHC-peptide and CD40L (T cells)/ CD40 (B cells)
- bound T cell delivers cytokines to complete activation of B cell
29
Q
How does the T-dependent B cell response begin?
A
- after maturation, B cells migrate to lymphoid follicles
- upon initiation of B cell response > B cell binds antigen via Ig receptor
> antigen internalized/ processed/ displayed via MHC II - T cells bind to MHC peptide complex on B cells through TCRs/ CD40
- some activated B cells form clusters (primary foci)/ complete differentiation > plasma cells
30
Q
What happens around 4 days after stimulation of the T-dependent B cell response?
A
- once plasma cells are differentiated, they migrate into medullary cord of lymph node
> produce large amounts of IgM antibodies in early phase of B cell response - some antigen-stimulated B cells do not form primary foci/ complete differentiation into plasma cells
> instead migrate to follicles of lymph nodes/ spleen to form germinal centers
31
Q
What happens in germinal centers of follicles?
A
- somatic hypermutation (SHM), followed by antigen selection
> affinity maturation- results in B cells with ↑ affinity BCRs/ antibodies - class-switching recombination (CSR) > production of antibodies of other isotypes
- low affinity and self-reactive B cells die
32
Q
How long does it take antibodies with mutations in variable regions to appear in circulation? (SHM/ CSR in germinal centers)
A
- 6-10 days after onset of immune response
33
Q
What cells remain at the end of the T-dependent B cell response?
(2 sets of long-lived cells)
A
- plasma cells in bone marrow/ gut > can last for lifetime
- memory B cells > circulate through lymphoid organs waiting for stimulation by same antigen
34
Q
What are the differences in primary/ secondary responses?
> immunologic memory
A
- primary response > low magnitude/ short duration/ peaks at 10-20 days
- secondary response > greater magnitude/ peaks in less time (1-4 days)/ more antigen-specific
35
Q
How do B cells contribute to enhanced secondary responses?
A
- primary response is characterized by a lag period
> primary foci B cells release IgM
> B cells from germinal center release IgM/ IgG - in secondary response > memory B cells available for immediate differentiation to high-affinity IgG secretion
36
Q
What are some functional differences between primary/ secondary B cells?
A
- Naive B cell > IgM predominates in early response
- Memory B cell > IgG predominates (IgA in mucosal tissue)
37
Q
What is the T-independent B cell response?
A
- does not require T cell help
- directed toward multivalent/ polymerized antigens
- mediated by B1/ marginal zone B cells (in spleen)
38
Q
What is an example of a type 1 T-independent B cell antigen?
(TI-1 antigen)
A
- LPS (bacterial lipopolysaccharide)
39
Q
How does antigen dose impact response to TI-1 antigens?
- TI antigens bind to innate PRR immune receptors on surface of B cells
A
- at high antigen doses > mitogenic for all B cells with responding innate PRR receptors > polyclonal activation > only a small minority of antibodies produced can bind to antigen
- at low antigen doses > innate immune receptors unable to bind enough antigen to stimulate B cell
> only B cells that bind to TI-1 antigen through their Ig receptors > elicit oligonal (few clones) B cell response > all secreted antibodies specific for TI-1 antigen
40
Q
What are some features of TI-2 antigens?
A
- many bound by complement component C3d
> activate B cells by cross-linking BCR/ CD21 receptors on B cell surface - are not mitogenic at high concentrations
41
Q
What types of B cells recognize T-independent antigens?
A
- B1 B cells > predominate in pleural/ peritoneal cavities/ produce mostly IgM antibodies
- marginal zone B cells (in spleen) > respond to blood-borne antigens/ produce mostly IgM antibodies
> high levels of CD21 > bind to antigens conjugated to C3d > important in protection against TI-2 antigens
