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Time Course of the
Primary Immune Response
Innate immunity
Acquired immunity
Ig Maturation
Journey of a B Cell
Contact Between the TCR and MHC/peptide:
Not All Peptides are Created Equal
The Two-Signal Theory of T-cell Activation
2
No response
1
No response
or Anergy
APC = Antigen-presenting cells
TCR = T-cell receptor for antigen
DC = Dendritic cell
CD80 = Co-stimulatory receptor
1
2
Activation
Two Major Functional T Cell Subsets
CD4+ T cell
Lck
z z
g d e
Ca Cb
CD4
Va
CD8+ T cell
Vb
MHC II
Lck
CD3
TCR
Ca Cb
CD8
peptide
APC
(1) Interacts with MHC class II expressing
cells (APCs)
(2) Helps B cells to synthesize antibody
(3) Induces and activates macrophages
(4) Secretes cytokines
z z
g d e
Va
Vb
MHC I
CD3
TCR
peptide
APC
(1) Interacts with MHC class I-expressing
cells (all nucleated cells)
(2) Kill MHC class I-expressing target cells
(3) Secretes cytokines
CD4+ T Cells Activate
Macrophages and B cells
Regulation of the Immune Response:
a Conceptual View
Immunity Activation
Suppression Tolerance
Regulation of the Immune Response:
a Conceptual View
Autoimmunity
Immunity
Immunodeficiency
Tolerance
Regulation of the Immune Response:
a Conceptual View
Autoimmunity
Immunity
Immunodeficiency
Tolerance
Antibodies:
Secreted or
Transmembrane
TCR: Transmembrane
DNA Rearrangement RemovesSequences Between V, D and J Segments
Figure 4-2
RNA Splicing Removes Sequences Between J and C Segments
DNA
RNA
Antigen-Independent B-Cell Development
Bone Marrow
1. DNA rearrangements establish the
primary repertoire, creating diversity
2. Allelic exclusion ensures that each clone
expresses a single antibody on the surface,
establishing specificity
3. Deletion of self-reactive clones establishes
tolerance
THE B CELL RECEPTOR
1. Bound antigen is internalized and presented
to T cells.
2. Bound antigen gives
signals to the B cell
to proliferate and
differentiate.
Signalling from the BCR
Lack of Btk causes
Bruton’s X-linked
agammaglobulinemia
(blocked at pre-B stage)
Antigen-Dependent B Cell Development
In Periphery (spleen and LN)
Antigen and TH cells give B cells two signals:
1) proliferate
2) differentiate
T-cell dependent responses are refined two
ways: 1) higher affinity antibodies
2) IgG/A/E (“switched”) isotypes
Two products of B cell development:
1) plasma cells secrete Ig (final effector)
2) memory cells respond to IIo antigen
T Cell-B Cell Communication
(B cells signal T cells by presenting Ag in
association with MHC II)
T cells provide 2 kinds of help to B cells:
1. Cell-cell signals from CD40L/CD40 and
other surface molecules.
2. Secreted cytokines
The Germinal
Center
1. Affinity maturation
a. Somatic hypermutation
b. Selection for high affinity clones
2. Isotype switch recombination
3. Peripheral tolerance
4. Final maturation to memory or plasma cell.
AFFINITY MATURATION IN THE GC
Proliferation + Somatic Hypermutation
Dark
zone
(Iterative cycles)
Ag(FDC) + T cell help
SURVIVAL
Light
zone
but
T help and no Ag
(eliminates low affinity clones)
DEATH
or
Ag and no T help
(eliminates self-reactive clones, giving tolerance)
1. Memory B cells
Surface Ig, usually IgG
High affinity for antigen
Long-lived, even in the absence of antigen
Respond rapidly to secondary stimulation
2. Plasma Cells
Secrete copious amounts of Ig, no surface Ig
Non-dividing
Some are short-lived, some become
long-lived in the bone marrow
Secreted
Antibodies
Function in
Various Ways
To Eliminate
Foreign Invaders
How T cells recognize antigen
Notion of immunological “SELF”
Skin graft transplantation compatibility
• Rejection by adaptive immune system T cell response
• Graft compatibility genetically determined
Extremely polymorphic trait -many alleles
Governed by genes of major histocompatibility
complex (MHC) that encode MHC molecules, the
principal targets of rejection
Differences in MHC molecules between individuals are
central to determining “SELF”
The selection process (Thymic “education”) has two stages
• First stage selects clones capable of recognizing self peptide in an
individual’s own MHC molecules - positive selection
• Second stage eliminates
overtly self reactive clones
with high affinity for self
peptide:MHC- negative
selection
*** (Self-peptides are used as a
surrogate for foreign peptides
since there are few non-self
peptides)
The TCR repertoire differs from individual to individual
• The specificity of self/non-self peptide binding to MHC molecules
determined by pockets that only bind certain amino acid side chains
• MHC genes are extremely polymorphic and alleles encode pockets
with specificities for different amino acid side chains
The TCR is specific
for both peptide
and MHC- A
complex ligand
Polymorphic
residues of
MHC
The definition of immunologic self is made by selecting
the clonal T cell repertoire on self-peptides bound to the
individual’s particular allelic forms of MHC molecules
The immune system makes this distinction by loading and
recognizing peptides in either class I or class II MHC
Challenge:
Cytosolic Virus
or Pathogen
Presenting cell:
Any cell
Peptide degraded in: Cytosol
Ingested Bacteria or
Endocytic Pathogen
Macrophage/DC
Extracellular Pathogen
or Toxin
B cell
Endocytic vesicles
Endocytic vesicles
Peptides bind to:
MHC class I
MHC class II (or I)
MHC class II
Presented to:
CD8 T cells
CD4 T cells (or CD8)
CD4 T cells
Activation of cell to
enhance pathogen
killing
Provision of help to B
cell for production of
antibodies
Effect on presenting Death of cell
presenting the
cell of T cell
viral antigen
recognition:
a1
N
a2
Structure of peptide-binding class I MHC domain
Codominant expression of MHC alleles
a=paternal haplotype
b=paternal haplotype
c=maternal haplotype
d=maternal haplotype
a/b
c/d
a/d
b/c
a/c
b/d
Polymorphic amino
acids that distinguish
alleles of MHC class
I molecules are
found primarily in
pockets that
determine peptide
binding or on the
surface that interacts
with the TCR
Because the TCR recognizes both peptide and MHC
molecule, T cell recognition of MHC-peptide is both
MHC restricted and specific for the immunizing peptide
In each of the 3 experiments the T cell is from a HLA-B7 person
who recovered from infection by virus “X”.
The APC target cell is either infected with virus X or Y and is from
an individual who is either HLA-B7 or HLA-B27
T cell
HLAB7
APC
Target killed: Yes
T cell
Peptide
HLAfrom
B7
virus X
APC
No
T cell
Peptide
HLAfrom
B27
virus Y
Peptide
from
virus X
APC
No
TCR repertoire selection and thymocyte
differentiation into CD4+ or CD8+ T cells
CD8 Staining
5%
80%
CD4-CD8+
3%
CD4CD8-
CD4+CD8
+
12%
CD4 Staining
CD4+CD8
-
Implications of Positive/Negative Selection
• Individuals with different MHCs have different
TCR repertoires
• T cells mature into CD4 or CD8 single-positive
cells as a result of positive selection.
Key molecular interactions between T
cells and APCs
CD3
TCR
MHC class II/
autopeptide
CD40
CD80
Activated T cell
CD40
CD40L
CD28
CD40
CD80
MHC
class II
(1) induction of cytokines/chemokines (IL-8, IL-12, TNF-a,
MIP-1a)
(2) stimulation of CD80 and CD86 expression and costimulatory function with activation of T cell growth
(3) augmentation of antigen-presenting function
Naïve CD4+ T cells differentiate into
Th1 and Th2 subsets
Th1 Cells
IL-2
IFN-g
TNF
IL-2
Antigen +
APC
Resting
CD4+ cell
“pTh”
Activated
CD4+ cell
IFN-g
(–)
IL-4
IL-10
(–)
IL-4
IL-5
IL-6
IL-10
Th2 Cells
Functions of T helper subsets
Functions of Th1 subsets
Th1 Cells
IL-2
IFN-g
TNF
IFN-g
(–)
IL-4
IL-10
(–)
• Activate macrophages/dendritic cells
augment antigen presentation
• induce delayed type hypersensitivity
(DTH) responses important in eradicating
intracellular pathogens (TB, leprosy, listeria
• mediate Th1 diseases (ie; rheumatoid
arthritis, multiple sclerosis and type I
diabetes
Functions of Th2 subsets
IL-4
IL-5
IL-6
IL-10
Th2 Cells
• Help B cells and induce humoral
immunity
• mediate allergic and immediate
hypersensitivity responses
• involved in antibody mediated
immune diseases like SLE and ITP
Antigen Processing and Presentation by B cells
ANTIGEN
BCR
(SmIg)
MHC Class ll
B cell
Peptide
Antigenic peptides
bind to MHC class II
molecules
Internalization of
antigen/Ig
Antigen binds specifically to BCR (surface membrane Ig),
is internalized into vesicles and cleaved into peptides which
displace and bind to MHC class II molecules. The
peptide/MHC complex is then transported to the surface
membrane.
T Cell- Macrophage Interactions
Fc receptor
TCR a,b
MHC class II
CD3
CD4
CD4 Th1 Cell
CD28
Macrophage
B7 (CD80)
IL-2
IL-12
CD40L
CD80
TCR a,b
CD4
IL-2
Receptor
MHC II
IFN-g
CD28
Activated Th1 Cell
CD80
IL-1
IL-6
IL-12
TNF
TGF-b
cytotoxic granules
Activated Macrophage
Maximum number of different types of HLA
molecules expressed on the cell surface
Nucleated
Antigen
cells
presenting cells
Class I (HLA-A)
Class I (HLA-B)
Class I (HLA-C)
Class II (HLA-DR)
Class II (HLA-DQ)
Class II (HLA-DP)
2
2
2
0
0
0
2
2
2
2
4
4
Total
6
16
(actually more)
Each of these MHC molecules selects its own T cell repertoire
that only recognizes peptides presented by that particular type
of MHC molecule
V. Cytokines you need to know
Innate
Adaptive
√√
√√
√
√√
√
√√
IL-2 (big family e.g. IL-7 & IL-15)
IL-4 (small family inc. IL-13)
IL-6 (large family inc. G-CSF)
IL-10 (growing family)
IL-12 (small family inc. IL-23)
IFN-g
IFN-a (large family)
√√
√√
√√
√√
√√
IL-1
IL-18
√√
√√
LT-a
TNF-a
CD40L
FasL
√
√√
√
√√
√√
TGF-b
Receptors
TGF-b (very large family)
√√
√√
Chemokine
Receptors
Chemokines (see Fig. 11.6)
Inflammatory
Non-inflammatory
√√
√√
√√
√√
Type I & II
Cytokine
Receptors
(Hematopoietin R.)
Toll (TLR) /IL-1
Receptors
TNF Related
Receptors
See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas
√
√√
√√
V. Cytokines you need to know
Innate
Adaptive
√√
√√
√
√√
√
√√
IL-2 (big family e.g. IL-7 & IL-15)
IL-4 (small family inc. IL-13)
IL-6 (large family inc. G-CSF)
IL-10 (growing family)
IL-12 (small family inc. IL-23)
IFN-g
IFN-a (large family)
√√
√√
√√
√√
√√
IL-1
IL-18
√√
√√
LT-a
TNF-a
CD40L
FasL
√
√√
√
√√
√√
TGF-b
Receptors
TGF-b (very large family)
√√
√√
Chemokine
Receptors
Chemokines (see Fig. 11.6)
Inflammatory
Non-inflammatory
√√
√√
√√
√√
Type I & II
Cytokine
Receptors
(Hematopoietin R.)
Toll (TLR) /IL-1
Receptors
TNF Related
Receptors
See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas
√
√√
√√
IL-2 activates T-cells in an autocrine manner
QuickTime™ and a
GIF decompressor
are needed to see this picture.
QuickTime™ and a
GIF decompressor
are needed to see this picture.
VIII. Chemokines
• Important chemoattractants
• Regulate steady state and inflammatory
leukocyte traffic
• Signal through G-protein coupled receptors
• Therefore good drug targets for big Pharma
• Two chemokine receptors serve as co-recpetors
for HIV infection (CXCR4 and CCR5)
Question:
How do viruses that don’t infect
“professional APCs” such as dendritic
cells elicit a primary immune response?
After all, virally-infected cells don’t
normally traffic to 2˚ lymphoid organs
“Classic” view of CTL response
against virus-infected cells
PVR expressed on
non-hematopoietic
cells.
Infection with
Poliovirus
Endocytosis of
virus, nuclear entry,
synthesis of viral
proteins in cytosol.
Presentation of
viral peptides on
MHC Class I to CD8+
cytotoxic T-cells
Proliferation of
cytotoxic T-cells
(CTLs)
Perforin/granzymemediated cell death
Cross-priming of exogenous
antigens by dendritic cells
•
PVR expressed on
non-hematopoietic
cells.
Infection with
Poliovirus
Cytopathic
changes; recognition
and phagocytosis
by dendritic cell
Phagosome-to-cytosol
protein export;
ubiquitin-mediated
proteolysis of viral proteins;
Presentation of peptide via
MHC Class I
Perforin/granzymemediated cell death
of DC; proliferation
of CD8+ CTL;
Killing of virus-infected
epithelial cells by CTL
Why do NK Cells Fail to
Recognize Healthy Cells?
Summary
1. For cytotoxic CD8 T-cells, ligation of the TCR by MHC I/peptide + co-stimulation
results in release of granzymes and perforin and/or FasL, leading to apoptosis
of the target cells.
2. Viruses evade host defense, in part, by down-regulating MHC Class I. Uninfected
dendritic cells circumvent this by “cross-priming”: phagocytosis of virus-infected
cell and presentation of “exogenous” viral antigens on MHC Class I.
3. The innate immune system has a rapid onset and recognizes molecular patterns
in a non-clonal fashion.
4. NK cells lack TCRs, but instead express both activating and inhibitory (e.g., KIRs)
receptors at their surfaces. The relative expression and ligation of these receptors
determines the outcome (i.e., killing or not) of the NK effector response.
5. Innate immune B-cells (e.g., B-1 cells and marginal zone B cells) recognize
carbohydrate antigens, secrete IgM, and are not long-lived.
6. Innate immune T-cells (gd T-cells, and NK T cells) recognize non-peptide antigens in
non-classical MHC-like molecules. They mediate cytotoxicity & rapid cytokine secretion.