4 Jan.

2024

Introduction to immunology

(Kim Minsoo)
kim.minsoo.7r@kyoto-u.ac.jp
 Schedule, test, assignments
4/Jan. 2024 On line
11/Jan
2nd TEST_ Ig G, M, A, E, D (5min, 10 questions)
18/Jan
Fill out _Immune ID card_ immune cell network

25/Jan.
Final exam. 70 min

1/Feb.
Student presentation
ID card as an “IMMUNE Cell”

NAME: James bond GET more than 10 stamps

ID: 007 Photo

Neutrophil Who you are?

Your role as an immune cell

Look like?
cell shape/structure

Release Histamine
Allergic response What is the role( or function) ?
etc.
“Immune cell ID cards"
“Immune cell ID cards"
Bring your ID cards on 13th Class (18th Jan.)

INTERACTION
CONNECTION
LINK
Components of Adaptive immunity

T cell
B cell

T
B

APC
(Antigen presenting cells)
 Characteristics of Adaptive Immunity

• Specificity - ability to distinguish between antigens

• Diversity - ability to respond to a wide variety of
antigens, generates enormous diversity of cellular
receptors and antibodies.
• Memory - Ability to recognize and quickly respond to
the previously encountered antigens. Nonreactivity to
self (self tolerance) -ability of the immune system to
tolerate “self” and recognize and destroy “non-self”
• Discrimination between self and Non-self- While both
innate and adaptive immune cells must discriminate
between self and non-self, the adaptive immune
system responds much more selectively to non-self.
Why are B cells able to produce such a
wide variety of antibodies?

Antigen Naive B cell

Epitope BCR (B cell receptor)

Directly attach to antigen

No relation with MHC

↑
100 billion types
 Diversity of Antibodies

• Combinatorial joining- The genomic recombination of V, D, and J

regions during lymphocyte development that gives rise to diverse
T-cell receptors, B-cell receptors, and antibodies.
• Somatic hypermutation- A high rate of mutation within
antibody-encoding genes that occurs in B cells following T-cell
activation. This mechanism generates antibodies that are then
screened for high avidity and affinity.
clonal selection : The process by which an antigen binds to the best-
fitting B-cell receptor, activating that B cell, resulting in the synthesis
of that specific antibody and clonal expansion.
 List of Nobel Laureates in Immunology
③ YEAR
P36 表3 LAUREATE Discovery
1901 Behring serum therapy against diphtheria
1905 Koch investigations and discoveries in relation to tuberculosis
1908 Ehrlich investigations in relation to antitoxin and immunity
Metchnikoff investigations in relation to phagocyte
1912 Carrel vascular suture and the transplantation of blood vessels and organs
1913 Richet his work on anaphylaxis
1919 Bordet discovery of complement
1930 Landsteiner discovery of human blood groups
1951 Theiler discoveries concerning yellow fever and how to combat it
1960 Burnet, Medawar discovery of acquired immunological tolerance
1972 Porter, Edelman discoveries concerning the chemical structure of antibodies
1977 Yalow development of radioimmunoassays of peptide hormones
1980 Snell, Dausset, Benacerraf discoveries concerning genetically determined structures on the cell surface that regulate immunological
reactions
1984 Jerne discovery of the principle for production of monoclonal antibodies
Kohler, Milstein theories concerning the specificity in development and control of the immune system
1987 Susumu Tonegawa discovery of the genetic principle for generation of antibody diversity
1990 Thomas, Murray discoveries concerning organ (Murray) and cell (Thomas) transplantation in the treatment of human disease

1996 Zinkernagel, Doherty discoveries concerning the specificity of the cell mediated immune defense
2011 Steinman discovery of the dendritic cell and its role in adaptive immunity
Hoffman, Beutler discoveries concerning the activation of innate immunity
 Antigen presenting cells

• DC capture antigen into cells that can present antigens

to naive T cells and to activate the lymphocytes.
• Macrophages present the antigens of phagocytosed
microbes to effector T cells, which respond by activating
the macrophages to kill the ingested microbes
• B lymphocytes internalize protein antigens and present
peptides derived from these proteins to helper T cells.
This antigen-presenting function of B cells is essential for
helper T cell–dependent antibody production.
• All nucleated cells can present peptides, derived from
cytosolic protein antigens, to CD8+ CTLs .
• Other cell types that express class II MHC molecules and
may present antigens to T cells include endothelial and
some epithelial cells.
Properties of antigen presenting cells
• Different cell types function as antigen-presenting cells to activate naive
T cells or previously differentiated effector T cells
Properties of antigen presenting cells

• The membrane-bound molecules of APCs that function

together with antigens to stimulate T cells.

• APCs secrete cytokines that play critical roles in the

differentiation of naive T cells into effector cells

• Toll-like receptors and other microbial sensors respond

to microbes →increasing the expression of MHC
molecules and costimulators → improving the
efficiency of antigen presentation and activating the
APCs to produce cytokines → all of which help stimulate
T cell responses.
Properties and Functions of Antigen-Presenting Cells

Class II Major Histocompatibility

Cell Type Costimulators Principal Function
Complex
Constitutive; increases with Constitutive; expression is Antigen presentation to
maturation; increased by IFN- increased with TLR signals, naive T cells in initiation of T
Dendritic cells
γ and T cells (CD40L-CD40 IFN-γ, CD40-CD40L cell responses to protein
interactions) interactions antigens (priming)
Antigen presentation to
effector CD4+ T cells in
Low or negative; increased by Expression is increased by
effector phase of cell-
Macrophages IFN-γ and T cells (CD40L-CD40 TLR signals, IFN-γ, CD40-
mediated immune responses
interactions) CD40L interactions
(T cell–enhanced killing of
phagocytosed microbes)
Antigen presentation to
Constitutive; increased by IL-4, Expression is increased by T
CD4+ helper T cells in
antigen receptor cross-linking, cells (CD40-CD40L
B lymphocytes humoral immune responses
and T cells (CD40L-CD40 interactions), antigen
(helper T cell–B cell
interactions) receptor cross-linking
interactions)
May promote activation of
Inducible by IFN-γ; constitutive in antigen-specific T cells at site
Vascular endothelial cells Low; may be inducible
humans of antigen exposure and in
organ grafts
No known physiologic
Various epithelial and
Inducible by IFN-γ Probably none function; possible role in
mesenchymal cells
inflammatory diseases
IFN-γ, Interferon-γ; IL-4, interleukin-4; LPS, lipopolysaccharide.
 B cell vs T cell
B cell T cell

B T

B cell recognize T cell recognize

variety of antigens only Protein antigens
• Proteins • Peptides
• Polysaccharides • MHC-peptide complex
• Nucleic acids
• Lipids
Development of B and T Lymphocytes

T cells recognize self-antigen

to undergo cell death

Naïve T cell migrate to lymph node and spleen

 T-Cell Receptors (TCRs)

• Reside in the plasma membrane

surface.
• Heterodimer receptor and accessory
proteins
• TCR recognize and respond to cell-
associated antigens and not to soluble,
cell-free antigens
• Antigen fragments must be presented
by antigen-presenting cells (APCs) on
the ends of MHC molecules.
• TCR recognizes and binds both antigen-
derived peptide and MHC to which
peptide is bound.
• Most T lymphocytes recognize only
short peptides.

TCRs play an essential role in both T cell development and activation.

Components of TCR
 Structure of the TCR

• Structurally similar to
immunoglobulin domains

• Two subunits, α and β, each have a

Constant region and Variable region

• Variable regions forms peptide

specific binding site

• Constant regions each contain

transmembrane regions

• Two TCR types, αβ and γδ, have

diverse antigen binding
characteristics
 Types of T Cells

Mature T cells are naïve

until activated by antigen
presentation.
Once activated, they
proliferate into effector cells
and memory cells.
• Effector cells carry out
specific functions to protect
host against foreign antigen.
• Three types: T-helper (TH)
and T regulatory cells,
cytotoxic T lymphocytes
(CTL).
 T-Helper Cells

Also known as CD4+ T cells.

Activated by antigen presentation with class II
MHC.
Most important types of T-helper cells:
• TH0—mature, naïve T cells; not yet
activated.
• TH1—help activate macrophages. secrete
cytokines （IFN , TNFetc)
• TH2—help B cells produce antibodies.
• TH17—assist in antibacterial responses.
recruit neutrophils.
• Treg—help control lymphocyte responses.
suppress immunity and inflammation.
The role of T helper cells

• Help activate B cells to become

antibody-secreting cells
• Help activate macrophage to
destroy any intracellular pathogens
multiplying within the
macrophage’s phagosome
• Help induce naïve Tc cells to
become effector cells that can kill
infected target cells
• Stimulate the activated DC that
activated them to maintain the DC
in an activated state
 Cytotoxic T Lymphocytes
• CTL are CD8+ T cells that have been activated by antigen presented on MHC-I
molecules of dendritic cells.
• Once activated, these CTLs can kill host cells that have been infected by
intracellular pathogens, such as a virus, are presenting cancer neoantigens
• After binding target, CTL kills target cell via the perforin pathway and an
apoptotic (programmed cell death, FasL-Fas Receptor) pathway.

Degranulation occurs and causes

pores (perforin) in target cell
membrane.
granzymes cause apoptosis
 Cytotoxic T Lymphocytes

The CTL secretes perforin that forms pores in the

target cell’s plasma membrane. These pores
allow the contents of the target cell to leak out
and granzymes to enter and induce apoptosis.
Th17 and Treg cells
 Other T cell subsets
γδ T cell (poorly understood)
• small subset of T cells
• reside in the skin and mucous membrane (intestine, vagina,
uterus,tongue…)
• Don’t recognize MHC associated peptide antigen
• Don’t require Antigen processing
• Cytokine secretion, killing infected cells, inflammatory disorder
• Primitive T cell

NKT cell
• Express TCR and NK cell markers
• Lipid antigen
T cell activation
Roles of T helper cells
• Help activate B cells to become
antibody-secreting cells
• Help activate macrophage to
destroy any intracellular pathogens
multiplying within the
macrophage’s phagosome
• Help induce naïve Tc cells to
become effector cells that can kill
infected target cells
• Stimulate the activated DC that
activated them to maintain the DC
in an activated state
T-Cell Activation

Requires binding a specific

antigen.
• Signal1: Occurs through antigen
presentation bridging MHC class on
the APC to the T-cell receptor
(immune synapse).
• Signal2: Initiates signaling cascade
involving other membrane-bound
proteins and intracellular
messengers. (costimulatory signal)
• Signal3: Cytokine release stimulate
the target T cells to differentiation
into effector or memory cells.
Cytokine-Receptor
 B-Cell Receptor
B cells must be activated by a
specific antigen.
• Cells then replicate and
differentiate into plasma cells
which secrete antibodies.
B cells have immunoglobulin
receptors (called B-cell receptors
(BCRs)) for the specific antigen
that will activate that particular B
cell.
Interaction with that antigen is
communicated to the nucleus via a
signal transduction pathway
similar to that described for T
cells.
 B cell activation
Antigen
Antibody to
BCR
Interaction with
T cells
Plasma cells
→Neutralization, opsonization
Exposure to
Naïve B cell Activated B cell
antigen

Memory B cell
→Initiate rapid response to
reinfection with same agent
B cells keep recirculating between lymph, blood and secondary lymphoid tissues.
B cells express BCRs on each cells. BCRs encounter antigen and internalize it.
B cells present the antigen to helper T cells on MHC molecules.
With T cell help, they proliferate and differentiate into plasma cells and memory
cells, which provide long term protection.
Effector B cells are called Plasma cell. (= > Antibody secreting cells)
 Antigen-Specific B-Cell Activation
T-cell-dependent B-cell activation.
• Involves interaction with T cells.
• Memory B cell formation
• High affinity antibody production
Shortcut!
T-cell-independent B-cell activation.
• T-independent antigens trigger B-cells to produce antibodies
without T-cell cooperation.
• Polymeric antigens with large number of identical epitopes (For
example, bacterial lipopolysaccharides).
• Antibodies produced have a low affinity for antigen.
• No memory B cells formed.
 T-Dependent Antigen Activation
Like T cells, require three signals.
• Antigen-BCR specific interaction.
• Co-stimulatory signals
• Activated T-helper 2 binds B-cell presented antigen and
secretes B-cell growth factors (cytokines).
B cell differentiates into plasma cell and memory cell.
Properties of Lymphocyte antigen receptors
TCR Immunoglobulin(ig)
Components α and β chains (most Heavy and light chains
common form of TCR)
Number of Ig domains One V domain and one C Heavy chain: One V
domain in each chain domain, three or four C
domains
Light chain: One V domain
and one C domain
Associated signaling CD3 and ζ Igα and Igβ
molecules
Affinity for antigen (Kd) 10-5–10-7 M 107–10-11 M

Changes After Cellular Activation

Production of secreted No Yes
form
type switching No Yes
Somatic mutations No Yes
 Major Histocompatibility complex

• A tightly linked cluster of genes whose products play

important role in intercellular recognition and in
discrimination between self and non-self.
• The proteins which are found on the membranes of almost
all the cells of human body are known as Major
Histocompatibility complex (MHC).
• Glycoproteins

T
MHC
 MHC
• Chromosome 6 (human) : Human leucocyte antigens (HLA complex)
• Chromosome 17 (mouse): H-2 complex
• Found on all nucleated cells in the body
• Develop Humoral and cellular immunity
• Bring antigen to the cell surface for recognition by T cells.
• Class1, Class2, Class3

Class2 Class1
Expressed on Antigen Presenting Cells Expressed on all nucleated cells

DP DQ DR C B A

centromere telomere
Class3
Not expressed on cell surface
 MHC molecules
MHC class I MHC class II
peptide
Class I MHC :
2 1 1 1 present in all the nucleated cells
Class II MHC :
2 2-micro- 2 2 present on dendritic cells,
globuln macrophages, and B cells

Cell membrane

←Top view of binding groove

of MHC proteins
✓ Class I and II molecules
exhibit polymorphism in
the peptide-binding
region
 MHC ClassⅠmolecule

• present in all the nucleated cells

• Member of the Ig superfamily
• 45 kDa glycoprotein α chain
• 12 kDa β2-microglobulin protein
• α chain passes through plasma membrane
• α1 and α2 domain α-helix and β-pleated sheet
form walls and floor of peptide binding site,
respectively
• The α1 and α2 domains form a cleft region that
binds an 8–10 amino acid–long peptide
fragment from an antigen
• Present peptides to CD8+ T cells
• Peptides derived from intracellular (foreign) or
endogenous (self) proteins
 MHC ClassⅡmolecule

• antigen-presenting cells (macrophages, B cells,

and dendritic cells )
• Member of the Ig superfamily
• Possesses Ig domains
• Heterodimeric
• A 33 kDa α chain
• A 28 kDa β chain
• Both chains pass through the plasma membrane
• A peptide-binding cleft is formed by the pairing of
the α1 and β1 domains
• Accommodates peptides of 13–18 amino acids in
length
• Class II MHC-peptide interactions: Usually derived
from exogenous extracellular processed antigens
• Present antigen peptides to CD4+ T cells
MHC-Peptide-TCR
MHC class I

The antigen receptors of T

cells recognize both the
antigenic peptide and the
peptide
MHC molecules
• Very small numbers of
peptide-MHC complexes are
capable of activating specific
T lymphocytes. TCR

2CKB (PDB)
Class11_Q &A
Please submit
2024/Jan/8 13:00 p.m.