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PABI 6100 Immunobiology > 3. Initiation of Immune Response > Flashcards

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
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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
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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
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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
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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
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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
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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
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8
Q

What is the first lymphoid structure to encounter antigens that enter tissue spaces?

A

Lymph nodes

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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
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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
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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)
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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
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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
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14
Q

What are the distinct stages of lymphocyte entry into lymph nodes from the blood?

A
  1. Rolling- interactions of selectins on T cells/ vascular addressins on HEV > rolling of T cells along surface of HEV
  2. Activation- chemokines on HEV activate receptors on T cells
  3. Adhesion- ↑ affinity of integrins on T cells for adhesion molecule on HEV > strong adhesion
  4. Diapedesis- T cells follow gradients of chemokines to pass through HEV wall
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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
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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
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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
  1. Activation- foreign peptide-self MHC/ TCR + co-receptor (CD4/ CD8)
    > partial T cell activation
  2. Survival/ Costimulatory signal- CD28 (T cell)/ B7 (APC)
    > effective T cell activation (↑ survival/ proliferation)
  3. 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
  1. binding of multivalent antigen to BCR (Ig receptors)
  2. binding of Th cell/ B cell through TCR/ MHC-peptide and CD40L (T cells)/ CD40 (B cells)
  3. 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

PABI 6100 Immunobiology (6 decks)

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