Download 20.380 S10 Introduction: the Immune System– the basics, inflammation in health

20.380 S10
Introduction:
the Immune System– the basics, inflammation in health and disease
20.400 spring 2008
1
Overview of the immune system
2
Two arms of immunity: the innate and adaptive immune systems
20.400 spring 2008
2
KEY EFFECTORS OF ADAPTIVE IMMUNITY
Diagram of how B lymphocytes, Helper T lymphocytes,
and Cytolytic T lymphocytes recognize particular antigens
and effect immunity has been removed due to copyright restrictions.
20.400 spring 2008
(Abbas)
2
THE CLONAL IMMUNE SYSTEM
•10^12 total T cells in adult human
•25-100 million distinct clones
•Only several thousand T cells at most respond to any
individual antigen (von Andrian and Mackay 2000)
•Precursor frequency of antigen-specific cells:
•CD8+ T cells: 1 in 200,000 cells specific for any given
antigen (0.0005% antigen-specific cells)
Arstila et al. Science 286, 958 (1999)
Blattman et al. J. Exp. Med. 195, 657 (2002)
20.400 spring 2008
3
The immune system:
evolved to eliminate
infectious disease
Katakai et al. JEM, 200,
783-792 (2004)
PERIPHERAL TISSUE
LYMPH NODE
LYMPHATICS
5
2
1
B
T
3
B cell
T cell
BLOOD
Dendritic cell
Source: Katakai, Tomoya, et al. "Lymph Node Fibroblastic Reticular
Cells Construct the Stromal Reticulum via Contact with Lymphocytes."
Journal of Experimental Medicine 200, no. 6 (2004).
4
B cell activation
Diagram of antigen recognition, B cell proliferation, and Ig secretion and
isotype switching has been removed due to copyright restrictions.
Lecture 20 Spring 2006
(Abbas)
13
Biology of dendritic cells in T cell activation
Classical pathways of antigen
processing and presentation:
CD8+ T cells
classical Class I
antigen loading
pathway
CD4+ T cells
Class II
antigen
loading
pathway
exogenous ANTIGEN
Lecture 20 Spring 2006
11
interactions in the lymph node
Three electron micrographs of T cells and dendritic cells interacting with
reticular fibers have been removed due to copyright restrictions.
T-cell activation
infected cell or
tumor cell
(1) antigen recognition
target cell
T
peptide-MHC
T cell receptor
(TCR)
Two electron micrographs removed due to copyright restrictions.
T-cell
(2) immunological synapse (IS) formation
T
T
5!
Grakoui et al. Science 285, 221 (1999)
Monks et al. Nature 395, 82-86 (1998)
The immune system: a distributed network
11
lymphocyte trafficking is “addressed” by combinations of
adhesion molecules and chemokine signals
Diagram of lymphocyte trafficking removed due to copyright restrictions.
There are four steps: rolling adhesion, tight binding, diapedesis, and migration.
See Figure 2-44 part 3 of 3, Janeway, Charles, et al. Immunobiology. 6th ed.
New York: Garland Science, 2005. ISBN: 9780815341017.
12
of TCR, costimulatory, chemokine, and cytokine signals that remain largely unexplored (36, 148). Moreover, the complete
Authors’ addresses
Summary: Directed cellular migrations underlie i
sequencing
has and
revealed
together specify unique microenvironments within
cutaneous
Daniel
J. Campbell1,2, Chang
H. Kim3, of the human and mouse
ization.genomes
Chemokines
their receptors (along
1,2
,
Eugene
C.
Butcher
many
‘orphan’
chemokine
receptors
whose
ligands,
expresmolecules)
are
central
to
these migrations, targ
and intestinal lymphoid tissues and direct expression of appro1
Laboratory of Immunology
and
Vascular
to tissues
and microenvironm
poorlyleukocytes
understood
(149).
priate combinations of adhesion and chemoattractant receptors. sion patterns, and function remainmature
Biology, Department of Pathology, Stanford
differentiation and function. The chemokine CX
addition,
very
the signaling pathways
Understanding these complex pathways of University
lymphocyte
School of In
Medicine,
Stanford,
CA, little
USA. is known about
CXCR4 play a central role in the migration of he
2
and transcription
factors that regulate
verychemokine
complexreceptors
tissue- are transiently ex
Center for Molecular
Biology and Medicine,
differentiation clearly requires further research, willTheundoubtand the
several
chemokines and chemotaxis: how the immune system gets around
Veterans Affairs Palo Alto Health Care System, Palo
Alto, CA, USA.
3
Laboratory of Immunology and Hematopoiesis,
Department of Veterinary Pathobiology and
Purdue Cancer Center, Purdue University, West
Lafayette, IN, USA.
Correspondence to:
Daniel J. Campbell
Benaroya Research Institute at Virginia Mason
1201
Ninth Avenue
Figure "Known and proposed
functions
for homeostatic chemokines and
Seattle,
WA 98101–2795
their receptors in lymphocyte
development,
trafficking, and function"
USA
has been removed due to copyright
restrictions.
Tel.: þ1 206 583 6525
Fax: þ1 206 223 7543
E-mail: [email protected]
stages of B- and T-cell development. In the periphe
T cells utilize the receptors CCR7, CXCR4, and
through specialized microenvironments within th
tissues, while effector and memory lymphocyte
patterns of adhesion molecules and chemokine
them to function within microenvironments and
inaccessible to naı̈ve cells. Here, we summarize t
and their receptors in the spatial organization of t
consider the implications for immune function.
The mechanisms of leukocyte homing
The mammalian immune system is design
tion while maintaining self-tolerance and
mediated pathology. In order to accompl
Acknowledgements
cells and tissues of the immune system are
We thank Tracy Staton and Gudrun Debes for
comments on the manuscript. E.C.B. is supto ensure the proper development, activati
ported by grants from the NIH and the
diverse leukocyte populations. Tissue- and
Veterans administration. D.J.C. is the recipient
selective leukocyte homing is the basis fo
of a postdoctoral fellowship from the Arthritis
Foundation. C.H.K. is supported by grants
and leukocyte responses to the chemoa
from The Eli and Edythe L. Broad Foundation
(chemokines) function prominently in t
and Leukemia and Lymphoma Society.
ways (1).
Leukocyte homing from blood to tissues
specialized post-capillary venules through a
Fig. 2. Known and proposed functions for homeostatic chemokines and their receptors in lymphocyte development,
trafficking,
andthe
function.
interactions
with
vascular endothelium
Receptors acting predominantly on B cells (red), T cells (green) or both (blue) are color coded. LN, lymph node; PP, Peyer’s patch.
sively in 2, 3). Initial interactions mediate
Immunological Reviews 2003
sion molecules, either selectins or low-affin
Campbell,
et al. Vol. 195: 58–71
13
66
ImmunologicalButcher
Reviews 195/2003
the
leukocytes
to roll along the endoth
Printed in Denmark. All rights reserved
presented on the endothelial surface trigg
Copyright ! Blackwell Munksgaard 2003
and avidity activation and mediate le
Immunological Reviews
the endothelial wall (4–6). Subsequen
0105-2896
unique combinations of chemokine/adhesion molecule
“addressins” lead immune cells to different tissue sites,
both in “healthy” immune responses and in
inflammatory diseases:
Reprinted by permission from Macmillan Publishers Ltd: Nature Immunology.
Source: Luster, Andrew D., Ronen Alon, and Ulrich H. von Andrian. "Immune
cell migration in inflammation: present and future therapeutic targets."
Nature Immunology 6 (2005). © 2005.
14
Luster, Alon, and von Andrian Nat. Immunol. 6 1182 (2005)
Diagram of chemotaxis directing cell migration has been removed due to copyright restrictions.
chemokines also direct cells to their appropriate locations within tissues
Source: Okada, Takaharu et al. "Antigen-Engaged B Cells
Undergo Chemotaxis toward the T Zone and Form Motile
Conjugates with Helper T Cells." PLoS Biology 3, no. 6 (2005).
Figure of T cell/B cell removed due to copyright restrictions.
Katakai et al. JEM, 200,
783-792 (2004)
Steps in the immune response to infection
17
innate immune sentinels
HIV illustration removed due to copyright restrictions.
18
http://www.northwestern.edu/newscenter/images/2008/12/hiv-illustration.jpg
infection site
in peripheral
tissue
(1) chemoattraction of
dendritic cells/DC precursors
to sites of infection/
inflammation
pathogen
resident DCs in skin
(3) DCs travel to
lymph nodes
APC
Electron micrograph of resident dendritic cells in skin
has been removed due to copyright restrictions.
peptide-MHC
(2) dendritic cells
collect antigen
and become
activated
Dendritic cells and
initiation of adaptive
immune responses
(4) DCs activate
lymphocytes by
cell-cell contact
5
5
Randolph, Angeli, and Swartz Nat. Rev. Immunol. 5 617 (2005)
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology.
Source: Randolph, Gwendalyn J. et al. "Dendritic-cell trafficking to lymph nodes through
lymphatic vessels." Nature Reviews Immunology 5 (2005). © 2005.
pattern recognition by the
immune system
infection site in peripheral
tissue
dsRNA
Diagram of gram-negative bacterium removed
due to copyright restrictions.
LPS
ssDNA, ssRNA
flagellin
Tri-acyl and diacyl
lipopeptides
Kawai and Akira, Curr. Opin. Immunol. 17 338-344 (2005)
www.invivogen.com
Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission.
Source: Kawai, Taro and Shizuo Akira. "Pathogen recognition with Toll-like receptors."
Current Opinion in Immunology 17, no. 4 (2005).
PAMP recognition
of microbes by
dendritic cells
Immune cells integrate many signals to
‘fingerprint’ pathogens:
dsRNA
LPS
Diagram from Science magazine removed
due to copyright restrictions.
ssDNA,
ssRNA
flagellin
Tri-acyl and
di-acyl
lipopeptides
Huang et al., Science 294 3870 (2001)
Kawai and Akira, Curr. Opin. Immunol. 17 338-344 (2005)
Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission.
Source: Kawai, Taro and Shizuo Akira. "Pathogen recognition with Toll-like receptors."
Current Opinion in Immunology 17, no. 4 (2005).
Lecture 20 Spring 2006
7
TLR signaling is likely one of the earliest steps in the host response to infection
22
what we typically think of as inflammation: recruitment of innate and adaptive immune cells to peripheral tissue sites:
The New England Journal of Medicine
inflammatory agent applied to epithelium:
Figure removed due to copyright restrictions.
See Figure 2 from Luster, Andrew D. "Chemokines — Chemotactic
Cytokines That Mediate Inflammation." New England Journal of Medicine 338 (2006).
Le Borgne, Dubois et al. Immunity 24
191-201 (2006)
Courtesy of Elsevier, Inc., http://www.sciencedirect.com.
Used with permission. Source: Le Borgne, Marie, et al. "
Figure 2. Chemokine Regulation of Leukocyte Movement.
Dendritic Cells Rapidly Recruited into Epithelial Tissues via
Chemokines are secreted at sites of inflammation and infection by resident tissue cells, resident and recruited leukocytes, and cyCCR6/CCL20 Are Responsible for CD8+ T Cell Crosspriming
tokine-activated endothelial cells. Chemokines are locally retained on matrix and cell-surface heparan sulfate proteoglycans, establishing a chemokine concentration gradient surrounding the inflammatory stimulus, as well as on the surface of the overlying
In Vivo." Immunity 24 (2006).
endothelium. Leukocytes rolling on the endothelium in a selectin-mediated process are brought into contact with chemokines retained on cell-surface heparan sulfate proteoglycans. Chemokine signaling activates leukocyte integrins, leading to firm adherence
and extravasation. The recruited leukocytes are activated by local proinflammatory cytokines and may become desensitized to fur-
Diagram explaining process of inflammation removed due to copyright restrictions.
Robbins and Cotran Pathol. Basis of Disease 7th ed.
24
recruitment of DCs: chemotaxis into inflammation sites
chemoattractants
bring monocytes and
DCs to sites of
infection
Two electron micrograph images removed due to copyright restrictions.
infection site
in peripheral
tissue
(1) chemoattraction of
dendritic cells/DC precursors
to sites of infection/
inflammation
pathogen
resident DCs in skin
(3) DCs travel to
lymph nodes
APC
peptide-MHC
Reprinted by permission from Macmillan Publishers Ltd: Nature
Reviews Immunology. Source: Randolph, Gwendalyn J. et al. "Dendritic-cell
trafficking to lymph nodes through lymphatic vessels." Nature Reviews
Immunology 5 (2005). © 2005.
(2) dendritic cells
collect antigen
and become
activated
(4) DCs activate
lymphocytes by
cell-cell contact
5
Randolph, Angeli, and Swartz Nat. Rev. Immunol. 5 617 (2005)
Antigen is one of (at least) two signals that must be delivered by a vaccine
+DC ACTIVATION
+ANTIGEN
•T CELLS TOLERIZED
•NO T CELL ACTIVATION
+ANTIGEN
+DC ACTIVATION
Signal 1 - antigen
Signal 2 - costimulation
Signal 3 - cytokines
•MAXIMAL T CELL
PROLIFERATION
•GENERATION OF FULL
EFFECTOR FUNCTIONS
•GENERATION OF MEMORY T
CELLS
Lecture 20 Spring 2006
12
(1) antigen carried to
lymph nodes:
ORCHESTRATION OF THE
PRIMARY IMMUNE RESPONSE
(3) Antigen-specific T and B cells
meet at follicular border:
(2a) B cells encounter antigen,
likely in follicles:
3.5 min
antigen
B cells
T cells
Figure from New England Journal of
Medicine removed due to copyright
restrictions. See Figure 3 from Ada,
Gordon. "Advances in Immunology:
Vaccines and Vaccination." New
England Journal of Medicine 345 (2001).
(Pape et al. Immunity 26 491 (2007))
(2b) T cells encounter antigen in T
zones:
pMHC
B cells
Source: Okada, Takaharu et al. "Antigen-Engaged B Cells
Undergo Chemotaxis toward the T Zone and Form Motile
Conjugates with Helper T Cells." PLoS Biology 3, no. 6 (2005).
Courtesy of Elsevier, Inc., http://www.sciencedirect.com . Used with permission. Source: Itano, Andrea A., et al.
"Distinct Dendritic Cell Populations Sequentially Present Antigen to CD4 T Cells and Stimulate Different Aspects
of Cell-Mediated Immunity." Immunity 19, no. 1 (2003).
Katakai et al. JEM, 200,
783-792 (2004)
PERIPHERAL TISSUE
LYMPH NODE
LYMPHATICS
5
1
2
B
T
3
B cell
T cell
BLOOD
Dendritic cell
Source: Katakai, Tomoya, et al. "Lymph Node Fibroblastic Reticular
Cells Construct the Stromal Reticulum via Contact with Lymphocytes."
Journal of Experimental Medicine 200, no. 6 (2004).
4
these data suggest that lymphocytes integrate a complex array
of TCR, costimulatory, chemokine, and cytokine signals that
together specify unique microenvironments within cutaneous
and intestinal lymphoid tissues and direct expression of appropriate combinations of adhesion and chemoattractant receptors.
Understanding
pathways of lymphocyte
The New England these
Journalcomplex
of Medicine
differentiation clearly requires further research, will undoubt-
growth/survival factors, but these aspects of their
biology
Eugene C. Butcher1,2,
remain largely unexplored (36, 148).1Laboratory
Moreover,ofthe
complete
Immunology and Vascular
sequencing of the human and mouse
genomes
has revealed
Biology,
Department
of Pathology, Stanford
many ‘orphan’ chemokine receptorsUniversity
whose School
ligands,
expres- Stanford, CA, USA.
of Medicine,
2
The Center
for Molecular
Biology and Medicine,
sion patterns, and function remain poorly
understood
(149).
Veterans
Affairs
Palo
Alto
Health
In addition, very little is known about the signaling pathways Care System, Palo
Alto, CA, USA.
and transcription factors that regulate3 the very complex tissue-
Adaptive immune cell effectors home back to infection site:
Development in primary
lymphoid tissues
Lymphocyte recirculation and
immune surveillance
Laboratory of Immunology and Hematopoiesis,
Department of Veterinary Pathobiology and
Purdue Cancer Center, Purdue University, West
Microenvironmental positioning
Lafayette,
and non-lymphoid tissue
homingIN, USA.
Correspondence to:
Daniel J. Campbell
Benaroya Research Institute at Virginia Mason
1201 Ninth Avenue
Seattle, WA 98101–2795
USA
Tel.: þ1 206 583 6525
Fax: þ1 206 223 7543
E-mail: [email protected]
Thymus
CXCR4/CXCL12
CCR9/CCL25
CCR4/CCL17/CCL22
CCR7/CCL19/CC21
Figure removed due to copyright restrictions.
LN/spleen
See Figure 2 from Luster, Andrew D. "Chemokines — Chemotactic
CCR7/CCL19/CCL21
Cytokines That Mediate Inflammation." New England
Journal of
CXCR4/CXCL12
Medicine 338 (2006).
Bone marrow
CXCR4/CXCL12
CCR9/CCL25
PP
CCR7/CCL19/CCL21
CXCR4/CXCL12
CXCR5/CXCL13
Figure removed due to copyright
restrictions.
Acknowledgements
See Campbell, Daniel J., Chang
H.
Kim, and
We thank Tracy
Staton and Gudrun Debes for
Eugene C. Butcher. "Chemokines
in on
thethe
systemic
comments
manuscript. E.C.B. is suporganization of immunity." ported
Immunological
195,and the
by grants Reviews
from the NIH
no. 1 (2003).
Veterans administration. D.J.C. is the recipient
of a postdoctoral fellowship from the Arthritis
Foundation. C.H.K. is supported by grants
from The Eli and Edythe L. Broad Foundation
and Leukemia and Lymphoma Society.
Fig. 2. Known and proposed functions for homeostatic chemokines and their receptors in lymphocyte development, trafficking, and function.
Receptors acting predominantly on B cells (red), T cells (green) or both (blue) are color coded. LN, lymph node; PP, Peyer’s patch.
66
Immunological Reviews 195/2003
Figure 2. Chemokine Regulation of Leukocyte Movement.
Chemokines are secreted at sites of inflammation and infection by resident tissue cells, resident and recruited leukocytes, and cytokine-activated endothelial cells. Chemokines are locally retained on matrix and cell-surface heparan sulfate proteoglycans, establishing a chemokine concentration gradient surrounding the inflammatory stimulus, as well as on the surface of the overlying
endothelium. Leukocytes rolling on the endothelium in a selectin-mediated process are brought into contact with chemokines retained on cell-surface heparan sulfate proteoglycans. Chemokine signaling activates leukocyte integrins, leading to firm adherence
and extravasation. The recruited leukocytes are activated by local proinflammatory cytokines and may become desensitized to further chemokine signaling because of high local concentrations of chemokines. The Duffy antigen receptor for chemokines (DARC),
a nonsignaling erythrocyte chemokine receptor, functions as a sink, removing chemokines from the circulation and thus helping
to maintain a tissue–bloodstream chemokine gradient.
Copyright ! Blackwell Munksgaard 2003
Immunological Reviews
0105-2896
58
molecular warfare involved in clearing infections:
Figure of chemical processes within a blood vessel removed due to copyright restrictions.
31
regulatory T-cells play a key role in preventing activation of immune responses in the steady
state and are thought to help regulate the close of immune responses in infection:
IFN
IL-10
IL-4 and IL-10
TH2 cell
IL-10
and
IFN
TH1 cell
Conversion
DC
IDO
ion
lat
du
CTLA4, TGF,
IL-10, cAMP,
adenosine and
granzyme B
M
od
ula
tio
n
du
lat
ion
Mo
od
M
n
tio
a
l
u
Microbial
products
Modulation
Mo
WS
Turning off the immune response as infection is cleared:
Natural
TReg cell
IL-10
Modulation
Induction
IL-10 and
TR1 cell TGF
Induction
IDO
Figure 1 | Regulatory T cells during infection. Various populations of regulatory T cellshave been shown to have a
Reviews | Immunology
role during infection. T helper 1 (TH1)-cell and TH2-cell populations can regulate each other viaNature
their production
of
+
+
+
cytokines. Naturally occurring forkhead box P3 (FOXP3)Reprinted
CD4 CD25
regulatory
cells (natural
TReg cells)
can limit
TH1by permission
fromTMacmillan
Publishers
Ltd: Nature
Reviews
and TH2-cell responses either indirectly by modulating antigen-presenting
cell (APC)
function
or directly
byand
cell–cell
Immunology. Source: Belkaid,
Yasmine.
"Regulatory
T cells
infection:
Belkaid
Nat.
Rev Immunol.
875 (2007)involve the release
contact.
Indirect
regulatory 7
mechanisms
of
transforming
growth
factor-B
(TGFB,
interleukin-10
a dangerous necessity." Nature Reviews Immunology 7 (2007). © 2007.
(IL-10) or adenosine, or the induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) by APCs
recognizing cytotoxic T-lymphocyte antigen 4 (CTLA4) on natural TReg cells. Direct regulation of effector T cells includes
32
anisms that
ue hypoxic
t for develhat have an
roving the
issues. We
ave evolved
anism that
gical studies
fects on the
in different
es.
unological
mediators
e factor 1α
d adenosine
3
.
Turning off the Rimmune
E V I E W S response as infection is cleared:
REVIEWS
role of hypoxia/adenosine
receptor signaling
Hypoxia
[O2]low
Inspired air
Po2 = 21 kPa (159 mm Hg)
A2AR
AMP
Lungs
Po2 = 20 kPa (150 mm Hg)
[O2]low
NT5
AK
Cyclic
AMP
Adenosine
HIF1α
A2BR
[Adenosine]hi
Immune cell Circulation
Po2 = 5–13 kPa (40 –100 mm Hg)
T cell
Inhibited production
of interferon-γ
Inhibited T-cell response
s
ny comparttissues14–19.
sion of the
g a hypoxic
med tissues,
ecause the
rect in vivo
poxic enviponses was
l-mediated
s a marked
ygenation.
of the anti-
TCR
Tissues
Po2 = 0.5–2.5 kPa (4–20 mm Hg)
(hypoxia)
Figure 1 | Low oxygen concentration in tissue
environments. Oxygen is inspired from the air; the oxygen
Sitkovsky
Rev
Immunol.
712
(2005)
in air is
21 kPa
(159 mm 5
Hg),
which
is a
tension (Po2)Nat.
concentration of 21%. When warmed air arrives in the lungs,
it loses some pressure: Po2 = 20 kPa (150 mm Hg). The
Reprinted
bycontinues
permission
Macmillan
oxygen
pressure
to from
decrease
in the Publishers
circulation:Ltd: Nature
Immunology.
13 kPa (100
mm Hg) Source:
in alveoliSitkovsky,
and 5 kPaMichail
(40 mmand
Hg)Dmitriy
Po2 =Reviews
Lukashev.
"Regulation
of
immune
cells
by
local-tissue
in veins that reach the heart. The oxygen pressure in the oxygen
tension:
HIF1and adenosine
receptors."
Nature
tissues
then decreases
with increasing
distance
fromReviews
Immunology
(2005).
2005.
= 0.5©–2.5
kPa (4–20 mm Hg).
the blood
vessels:5Po
2
Figure 3 | The hypothesis: role of hypoxia in local tissues
in the regulation of T cells in inflamed and hypoxic
areas. We think that excessive collateral immune damage to
the local-tissue microcirculation, and therefore to the oxygen
(O2) supply, creates deepening tissue hypoxia, which functions
as a signal to stop immune responses. Hypoxia, in turn,
inhibits adenosine kinase (AK) and upregulates 5′-nucleotidase
(NT5) activity, which results in the accumulation of extracellular
adenosine. Adenosine signals through the immunosuppressive
adenosine receptors A2AR and/or A2BR at the surface of
surrounding activated T cells, and it downregulates T-cellreceptor (TCR)-mediated responses in a delayed negativefeedback manner. The regulatory effects of hypoxia-inducible
factor 1α (HIF1α) on T cells remain to be directly established,
but it is expected that the increased expression of HIF1 in
response to hypoxia will also be inhibitory.
HIF1 is a het
consists of the con
and the oxygenIn the presence o
hydroxylation of
and 564 of HIF1α,
domain, is catalyse
containing protein
a contribution fro
HIF1α is subseque
degradation that
tumour-suppresso
radation of HIF1α
low levels under n
hypoxic condition
PHD3 are, in turn
tia homologue 1A
degradation77 (FIG
mechanism ensu
under hypoxic co
moxic conditions
and activity of the
transcription of m
ing those encodin
poietin, adrenom
vascular endothel
In addition, th
be negatively regu
gine residue at po
dependent hydrox
which inhibits th
its co-activators, p
Induction of immunological
memory (the basis of vaccination)
Figure removed due to copyright restrictions.
See Kaech, Susan M. and Rafi Ahmed. "CD8 T Cells
Remember with a Little Help." Science 300, no. 5617 (2003).
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