Generation of the Adaptive Immune Response
IMM250F Immunity and Infection (Ch. 5)
Jasty Singh
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Generation of the Adaptive Immune Response
This Chapter: How the adaptive immune response is generated
Video 1: The activation of naïve lymphocytes – a multi- step process
Video 2: Secondary lymphoid tissues: Getting immune cells and antigens together
The activation of naïve lymphocytes:
A multi-step process
Where do lymphocyte maturation and activation happen?
Primary lymphoid tissues:
• Where lymphocytes ‘mature’
• Antigen receptors are first expressed
• Central tolerance is established
• B cell precursors mature in bone marrow
• T cell precursors mature in thymus
Secondary lymphoid tissues:
• Wheremature,naïvelymphocytesmeet antigens, become activated
— Lymph nodes, Spleen, Mucosa- associated lymphoid tissue, Skin- associated lymphoid tissue
The multi-step activation sequence
Engagement of antigen by antigen receptors
Costimulatory signal received by naïve lymphocyte through interaction with another immune cell
Cytokines are needed for:
• Proliferation
• Differentiation into effector
cells and memory cells
Each step involves intracellular signalling
Receptor Engagement
– involved at each step
• Engagement of a cell surface receptor transmits a signal to the inside of the cell
• New cell behaviour is induced by the signal (e.g. proliferation, differentiation)
Only dendritic cells can do everything required to deliver Signal 1 and Signal 2:
o Internalize pathogens and pathogen products
o Process internalized proteins and present peptides on both MHC class I and MHC class II molecules
o Express the key costimulatory molecule B7 which interacts with CD28 on the naïve T cells
Signal 3 IL-2 is important to induce proliferation of the cells
— CD4+ T cells makes its own
(‘autocrine’)
— Th effector makes it for naïve
Naïve T cell activation
CD8+ T cell
(Other cytokines influence differentiation→more on this later)
Only ‘mature’ DCs that have detected PAMPs/DAMPS can costimulate naïve T cells
Example for CD4+ T cell activation
• DCs express B7 only AFTER PRR-mediated detection of PAMPs/DAMPs induces them to mature
• B7 expression therefore indicates that the antigen being presented is associated with something that is a threat
Mature dendritic cells interpret the tissue environment for naïve T cells
For CD4+ T cell activation
DCs reports to the T cells regarding what is out in host tissues:
1) “This is what’s out in the tissues right now”
2) “It is a threat, so if you recognize it, get ready to respond”
Most naïve B cells require Th for activation
For Naïve B cells:
o Signal 1: BCR is engaged by
specific antigen
o Binding of antigen to the BCR triggers internalization, processing and presentation of peptide on MHC Class II
o Antigen-specific Th recognizes peptide- MHC class II on B cell so the two cells ‘dock’ together to form a TH-B conjugate
o Signal 2: Costimulatory contact between CD40 on B cell and CD40 ligand (CD40L) on Th cell
TH-B conjugate
o Signal 3: Th-derived cytokines help induce proliferation of the B cell and differentiation into plasma cells
(they also influence the ‘class’ of antibody the plasma cells make; more later)
Is it worth launching an adaptive response? The innate response provides the answer
Immature DC senses threat to host through detection of PAMPs/DAMPs associated with the presence of an antigen
Mature DC provides costimulatory contacts to activate naïve antigen-specific T cells
Antigen-specific Th provides costimulatory contacts to naïve antigen-specific B cell
Adaptive responses are only launched against an entity that is both foreign (‘non-self’) AND a threat to the host
Summary of components required for naïve lymphocyte activation
Secondary lymphoid tissues:
Getting immune cells and antigens together
Logistical challenge of lymphocyte activation
Activation of a naïve T cell specific for antigen X requires co-localization of:
• AntigenX
• Dendriticcell
• NaïveTcellspecificforX
Activation of a naïve B cell specific for antigen X requires co-localization of:
• AntigenX
• Naïve B cell specific for X
• Th effector specific for X
The frequency of lymphocytes specific for a given antigen X is very low (1 in 10,000 or less)
Challenge: How to effectively co-localize all these required elements?
Solution:→Secondary lymphoid tissues
Effectively co-localize antigens, DCs, lymphocytes required for the activation of naïve T and B cells
Secondary lymphoid tissues
Where lymphocytes become activated
Mucosa-associated lymphoid tissues • Facilitate local responses to pathogens that breach the mucosa
Nasopharynx- associated lymphoid tissue
Bronchi- associated lymphoid tissue
Gut- associated lymphoid tissue
Lymphocyte Recirculation
• Naïve lymphocytes continually migrate from blood circulation into secondary lymphoid tissues then back again into blood
• A naïve cell recirculates until it is either activated by specific antigen or dies (lifetime ≈ several weeks)
• IF a lymphocyte is activated it proliferates and differentiates in the secondary lymphoid tissue
Lymph nodes
• Facilitate systemic responses to pathogens in tissues
• Facilitatessystemicresponse to blood-borne pathogens
Adapted from Primer to The Immune Response, 2e. Copyright © 2014 Elsevier Inc.
Lymph nodes
Lymphocytes in the spleen monitor antigens in the blood
Pathogens may enter the blood via:
o Insect bites, snake bites
o Puncture wounds
o Contaminated needles for i.v. injection
o Placental transfer from mother to fetus
o Uncontrolled local infection in tissues
Internal architecture of spleen gathers different cell types in adjacent regions
T cell/DC area is like sleeve around arteriole B cell follicles encircle the T cell area
Lymphocytes (naïve, effector) exit via splenic vein
How do tissue antigens get to lymph nodes?
Lymph: fluid found in tissues due to constant leakage from blood capillaries
Lymphatic capillaries take up (‘drain’) lymph and contents (including antigens) from tissues to be delivered to lymph nodes
Nodes closest to a tissue site are the site’s ‘draining lymph nodes’
Lymphatic vessels connect to major veins leading to the heart so lymphatic and circulatory systems are connected
The lymphatic system
o Lymphatic system: Body-wide network of lymphatic vessels as well as the lymph nodes positioned along these vessels
o Connects to blood circulation via thoracic duct
(not part of lymphatic system)
(not part of lymphatic system)
Rockson, SG et al. Nature Reviews Disease Primers 5: 22 (2019) [with minor modification to left image]
Disruption of lymphatic flow results in swelling due to build up of fluid in tissues (lymphedema)
Damage to lymphatics from cancer treatment is a common cause of lymphedema
No need to memorize these!
Antigen-loaded dendritic cells can migrate to lymph nodes
Dendritic cells in the skin (‘Langerhans cells’)
• Skinandmucosaltractshavehigh levels of pathogen exposure
• These vulnerable tissues are densely populated with dendritic cells
• Experts at antigen uptake and sensing of PAMPs/DAMPs by PRRs leads to maturation
• Mature dendritic cells with captured antigen become mobile and travel via lymphatic vessels to local lymph nodes
• Once in the lymph node the dendritic cells present antigen to naïve T cells and provide costimulation
Immature DC is not mobile
Mature DC is mobile
To local lymph node
Internal architecture of the lymph node
Lymph, Antigens, Mature DCs from tissues
Bring lymph and contents into a lymph node
Follicular dendritic cell; traps antigens on cell surface so they remain longer in node (unrelated to DCs that activate T cells)
B cell follicle
Takes lymph and contents away from a lymph node
Video (2min:31s) ( , M.Sc. BioMed Communications):
Movie: Encounters between immune cells in the lymph node during infection
Or via Dept. IMM website: http://www.immunology.utoronto.ca/immunology-videos
Naïve lymphocytes and the lymph node
Summary: Off-site activation of lymphocytes leads to effector function at infection site
o Naïve lymphocytes migrate continually from blood to secondary lymphoid tissues and back again to blood (‘lymphocyte recirculation’)
– Maximizes the chance a lymphocyte will meet its specific antigen
o Effector T lymphocytes (Th, CTL) and antibodies leave secondary lymphoid tissues, travel through the blood and then they exit from the blood into sites of inflammation
Th and CTL need to be reactivated at infection site but no longer need costimulation
Clonal expansion in lymph nodes can often be felt clinically
Activated lymphocyte
Clonal selection
+ and expansion in =
draining lymph nodes
Swollen lymph nodes
Images: left, Primer to The Immune Response, 2e. Copyright © 2014 Elsevier Inc ; right, YouTube, https://www.youtube.com/watch?v=LjDAidSVs5A
Return to homeostasis after infection is cleared
The adaptive immune response has natural inhibition mechanisms that provide negative regulation
Antigen-induced lymphocyte proliferation (clonal expansion) is followed by natural cell death once pathogen is cleared
Lymphocyte numbers remain steady
Memory lymphocytes:
• Some take up residence at sites of inflammation and remain after infection is cleared
• Others recirculate through secondary lymphoid tissues (like naïve cells), as well as through sites of inflammation
A comparison of selected properties of naïve, effector and memory lymphocytes
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