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IMM250F Immunity and Infection
创建日期：2024-05-22 17:46:46
所属分类：生物biology
标签： IMM250F
Immunity and Infection

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Generation of the Adaptive

Immune Response
IMM250F Immunity and Infection
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:
• Where mature, naïve lymphocytes meet
antigens, become activated
— Lymph nodes, Spleen, Mucosa-
associated lymphoid tissue, Skin-
associated lymphoid tissue

The multi-step activation sequence
Signal 1:
Engagement
of antigen by
antigen
receptors
Signal 3:
Cytokines are needed for:
• Proliferation
• Differentiation into effector
cells and memory cells
Signal 2:
Costimulatory signal received
by naïve lymphocyte through
interaction with another
immune cell
Each step involves intracellular signalling
Intracellular Signalling – 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)
Receptor
Engagement
New Cell
Behaviour
Naïve T cell activation
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
CD8+ T cell
(Other cytokines influence differentiation → more on this later)
Only ‘mature’ DCs that have detected
PAMPs/DAMPS can costimulate naïve T cells
• 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
Example for
CD4+ T cell
activation
Mature dendritic cells interpret the
tissue environment for naïve T cells
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”
For CD4+ T
cell activation
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 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)
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
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:
• Antigen X
• Dendritic cell
• Naïve T cell specific for X
Activation of a naïve B cell
specific for antigen X requires
co-localization of:
• Antigen X
• Naïve B cell specific for X
• Th effector specific for X
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
The frequency of lymphocytes specific for a given
antigen X is very low (1 in 10,000 or less)
Adapted from Primer to The Immune Response,
2e. Copyright © 2014 Elsevier Inc.
Where lymphocytes
become activated
Mucosa-associated
lymphoid tissues
• Facilitate local
responses to
pathogens that
breach the mucosa
Nasopharynx-
associated
lymphoid tissue
Spleen
Lymph
nodes
Lymph nodes
• Facilitate systemic responses
to pathogens in tissues
Spleen
• Facilitates systemic response
to blood-borne pathogens
Bronchi-
associated
lymphoid
tissue
Gut-
associated
lymphoid
tissue
Secondary lymphoid tissues
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
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
Lymphocytes in the
spleen monitor
antigens in the blood
• 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)
No need to memorize these!
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
Rockson, SG et al. Nature Reviews Disease Primers
5: 22 (2019) [with minor modification to left image]
Antigen-loaded dendritic cells can migrate to lymph nodes
• Skin and mucosal tracts have high
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
Dendritic cells in the skin (‘Langerhans cells’)
• 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
To local lymph node
Immature DC
is not mobile
Mature DC
is mobile
Takes lymph and contents away from a lymph node
Video (2min:31s) (Heather Ambraska, 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
B cell follicle
Follicular dendritic
cell; traps antigens
on cell surface so
they remain longer
in node (unrelated
to DCs that activate
T cells)
T cells
DC
Lymph,
Antigens,
Mature DCs
from tissues
Internal architecture of the lymph node
Bring lymph and contents
into a lymph node
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
Infection
Clonal selection
and expansion in
draining lymph
nodes
+ = Swollen lymph nodes

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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MOEC0021 STA 106 ENGG 1300A ENGG 1300 OLET1139 STAT 3503 STAT 206 FEM11149 ELEN 4720 COMP20003 SOLA1070 CS574 C11CS LINB29H3 MAST90083 ECON7200 STAT 610 LINB29 DSM-5 COMP3161 EEEN40010 MATH 4431 K353 STA 3386 IERG4300 COMS W4167 ENG5298 AMME 2302 CS3910 COMPSCI 320 STATS 369 GR5242 COSC 328 CSCI435 MGTS1301 INFS2200 COMP3900 CIS 375 Module AE03 COMP3121 CS260 HAM503 MGMT5050 INT3075 COSC 285 GEOL0029 GEGE2X01 STAT1201 MATH1061 MMF1941H STAT 5060 CS 520 COMP 4320 MSIN0104 000T FINS3648 ECMT2160 ECON4003 Phys 129L CSE 142 CS 3130 MGEB01 EECS 340 Finance (20443/20444) ECMM149 COMP5310 EEEN60180 CSC 111 AT2 CSCI 4430 STAB57 MA/CSC 427 MATH322 D100 CSCI544 CITS3004 CI6227 CSE 565 APCO 1P01 852L1 ELEC S411F COMP3207 STATS330 ECON7530 FIT5149 CSI4104 CMPT 371 COMP201 SEHS4696 FI4003 MATH6182 CG1 WS MATH401 MGT 205 QTM 110 COMP 0137 MACE12201 FIT5210 ECE 544 BISM7206 HUDM 6055 ECON3203 STATS 210 MSCI 570 MATH6173 COMPSCI4039 Accounting COM3503 AOE2024 ECON213 PSYC10004 Control Data 100/200A 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MAS316/414 ACCT2522 MSIN0181 ATMS 201 COMP3425 MATH7861 SOLA2060 MA 325 7CCEMCTH ECON 432 INFT2051 SOLA 2060 ECOS2002 Stats141XP BIOA02H3 S2022 MA4601 K5 COMP5329 EG 284 IB3A70 WECO1020 COMP3027 Energy ACS61011 MAST20026 STAT 533 MATA31 ENVS257 BEM2031 EC 486 COMP0172 CS3214 EECE5644 IB2B20 COSC2536 COSC1147 COMP6214 5CCM242A COMP0130 AMME2000 MTMG50: EG238 ACF6006 QBUS2810 COSC2391 ECON7560 MATH377 STA305 CS 486 COMP1117B EL648 ELEC3909 ECON 241 COMP 4901W BUSI4428 ENEN20002 ENGN4524 ELEC3115 CSC 413 PSYC 100B ECON1002 MATH256 ANSC20005 MTHS2008 MATH40082 COSC 2406 FIT3174 STA 238 CMT202 Differential Equations MTHM017 GARCH 101 MATH2069 CSC336S ACSC12 ETF2121 CEME 2001 DB B474F ARHT1001 EECS 3311 3220 STATS 786 CS 484 COMP20008 MATH4091 ECE 455 CSCI 204 BUS B200F BA 875 BU5562 COSC 1147 X11 GEOG 101 IMM250F CSE 584A MATH38172 LAB 4 ELEC5882M FINS5523 EE 430 COMP 465 6CCS3PRE 7CCSMNSE FINANCE ACMB02H3 ENGG2112 ELEC5616 SCM B371 CHEM3120 CS22 ECMT2130 MAST30011 ADSPBF706 CENG0013 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