Transcript TCR

Immunology Course-General Principles
1. Repetition is good, especially in different contexts.
2. As good students, you are accustomed to mastering “the syllabus.”
At least in this course, you can’t. The syllabus is an illusion, it
does not truly exist.
3. It is important to learn the basics, the “party line.”
4. There is no party line; it keeps changing.
“Do I know the material?”
Simple test to determine whether you have mastered the material:
If you can explain the underlying concepts to the naïve (but motivated)
student, you’re heading in the right direction. Therefore: learn what
questions to ask.
Immunology-The Whirlwind Tour
Time Course of the
Primary Immune Response
Innate immunity
Acquired immunity
Ontogeny of the Acquired Immune System
Step 1. Lymphocytes develop in the bone marrow and thymus
Step 2. Naïve lymphocytes circulate in the blood and lymph
Step 3. The primary immune response occurs in the lymph nodes
and spleen
Step 4. Lymphocytes exit the lymph nodes and spleen
and become effector lymphocytes--they produce antibody (B cells)
or become competent to kill (CD8+ T cells)
Stages in the Development of a Primary
Immune Response
Step 1. The immune repertoire develops
Lymphocytes develop early in life in the 1° lymphoid organs
(bone marrow and thymus) and are competent to respond to a broad array
of antigens. This process is first stochastic in nature and then becomes
regulated by the MHC through positive and negative selection.
Ig Maturation
Antibody (Ig) and TCR are the Only Genes
that Undergo Somatic Cell Recombination
Antibodies: Secreted or
Transmembrane (BCR)
TCR: Transmembrane
Journey of a B Cell
What Happens in the Thymus?
Ordered TCR gene rearrangement and TCR expression
Ordered expression of surface molecules:
CD2
CD4 and CD8
CD3 and the TCR
Thymocyte Education: Selection of the T cell repertoire
Negative Selection
Positive Selection
Thymic Development
Bone marrow
Periphery
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
“Educated, but naïve”
What Happens During a
Primary Immune Response?
The Primary Immune Response-Input (APCs) and Output
(Lymphocytes et al.)
Three Types of APCs
The Itinerant Dendritic Cell
Functional Anatomy of a Lymph Node
Ag-loaded
APC
Naïve
T-cell
Effector or
Memory T-cell
The Clonal Selection Theory
Naïve state

Ag encounter

Clonal expansion

Functions of MHC I and II
Structure of Peptide-binding
Class I MHC Domains
a1
N
a2
Contact Between the TCR and MHC/peptide:
Not All Peptides are Created Equal
Contact Between the TCR and MHC/peptide:
Not All MHC Molecules are Created Equal
Polymorphisms
The “Fit” Between MHC Molecules
and Peptide Defines MHC Restriction
Polymorphisms within the MHC account for
the variability of the immune response
between individuals
T Cell Receptor for Antigen (TCR):
One TCR is Specific for One Antigen
Antigen
Recognition
T cell
Activation
The B Cell Receptor for Antigen (BCR)
Two Major Functions:
1. Bound antigen is internalized
and presented to T cells.
2. Bound antigen triggers signals
in the B cell to proliferate and
differentiate.
The “Immunologic Synapse”
QuickTime™ and a
Sorenson Video 3 decompressor
are needed to see this picture.
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
CD8+ CTLs Kill Viral-infected Cells
Major Lymphocyte Subsets in Peripheral
Blood and Selected Effector Functions
T cells
gd
B cells
Ab production
Ag presentation
CD8
Cytotoxicity Cytotoxicity
IFN-g secretion
Innate
immunity
CD4
Help to B cells
Help to CD8 T cells
Cytokine secretion
Macrophages activation
Regulation of the Immune Response:
a Conceptual View
Immunity
Tolerance
Activation
Suppression
Autommunity
Immunodeficiency
Systemic Lupus Erythematosis (SLE):
AnAutoimmune Disease
Clinical Manifestations of
Rheumatoid Arthritis