Chapter 8
B/T cell
development
B
T
Innate
immunity
Pattern
recognition
B/T cells
BCR/TCR:
epitope recognition
Gene rearrangement of AgR
Adaptive
immunity
Gene rearranged receptors
BCR/TCR:
Ag recognition
Extracellular Ag
Epitope
MHC-restriction
Intracellular Ag
Structure
Techniques
One cell one Ag-specific receptor
Clone
Fate
細胞差異
T/B: Rearranged AgR
T: MHC restriction
Adaptive immunity
Four characteristics
1. Antigen specificity
2. Diversity
3. Immunological memory
4. Self tolerance
Foreign (non-self) Ag
Self Ag
(encoded by the
host’s genome)
Aim of development
Production of AgR
1. Productive rearranged AgR
2.
Functional Ag recognition
3. Self tolerance
Self Ag?
MHC-restricted?
2
Hematopoiesis
Central lymphoid organs
Microenvironment
Commitment
Productive rearrangement?
Cell survival & death
B-cell development
T-cell development
Positive & negative selection
Fate
Self antigen
Before or after gene rearrangement of AgR ?
Development of B cells
Microenvironment
Stromal cells
Adhesion molecules
Chemokines & R
Cytokines & R
The dependence on
bone marrow stromal cells
Cell-cell
interaction
Early stages
B cell commitment
SDF-1
Constitutive production
Migration
Gene rearrangement
Gene rearrangement
Loop
Ig gene rearrangement & B cell stages
Proliferation
Antibody structure
Protein-regulated gene rearrangement
Cell survival or death
One cell one Ag-specific receptor
Allelic
exclusion
Self-reactivity
Fate
The presence of autoreactive lymphocytes in periphery
Low frequency of
Ag-specific B cells
B-cell development
T
B cell commitment
BCR rearrangement
Cell survival & death (BCR, self tolerance)
Stromal cell-dependent (Spatial regulation)
Temporal regulation of protein expression
Proteins:
receptors, cytokines, TS factors, recombinase, ..
Protein-regulated gene rearrangement
One cell one AgR
Cell survival & death
T cell development
Self MHC restriction
Self tolerance
Cells
Microenvironment
T cell development
Thymus
Epithelial cell
network:
thymic stroma
gdTCR
ab TCR genes
abTCR
or
gdTCR ?
b
Developmental
control of
gd T cells
Ordered sequence
Repeated rearrangements can rescue nonproductive VaJa joins
a gene rearrangement induces d gene deletion
T cell commitment
R: Notch 1
T cell development
Gene
rearrangement
Cortex
Medulla
Positive selection : MHC restriction
Negative selection : Self tolerance
33
Self MHC restriction
T cell development
MHC
Positive selection : MHC restriction
Negative selection : Self tolerance
MHC
Gene
locus
H-2k
37
H-2k
親代來源
基因
38
Analyze all the possible types of MHC class I
and II restriction for CD4 T and CD8 T cells
developed in an MHCbxk F1 hybrid mouse.
39
Ch6 section 6-12
MHC: co-dominant
d/k
40
?
41
TCR: MHC restriction
MHC haplotype
Ch6 section 6-12
MHC polymorphism
個體獨特性
MHC polymorphism
Alleles / locus
Formula: 100(DPa) X 100(DPb) X 100(DQa) X 100(DQb)
X 100(DRa) X 100(DRb) X 100(A) X 100(B) X 100(C) =1018
Variability of MHC alleles
MHC I
Peptide presented on
MHC I/II
MHC II
MHC-binding ability of peptides
Multiple epitopes
46
MHC-restricted presentation of antigenic peptides
d/k
47
Positive selection : MHC restriction
H-2k
Self MHC restriction
3
2
48
d/k
Self MHC restriction
3
6
2
8
49
MHC and immune responsiveness
Flow cytometry: immunostaining
51
T cell subsets in central and peripheral organs
Normal
Flow cytometry: immunostaining
52
Hybridoma
Low frequency of
Ag-specific T cells
High frequency
TCR transgenic mice
TCR transgene
T cell clone
53
Flow
54
Positive selection :
MHC restriction
MHCI-CD8 T
Cortex
MHCII-CD4 T
Techniques
基因剔除鼠
Knock-out
mice
56
Knock-out
mice
57
黑
白
Knock-out
mice
Knock-in
mice
58
Application of Tg & KO mice system
?
Positive
selection
MHC II restriction:
Interaction of CD4 with MHCII
KO
Host
KI
KI
59
KO Lethal effect
Inducible
knock-out
mice
Tissue specificity
Cre/lox system
Enzyme
(recombinase)
in other tissues
60
Immunodeficient mice
Defective gene repairing system
Severe combined immunodeficiency
Genetic defect of a gene coding for
transcription factor Wnt required for
terminal differentiation of
cortical epithelial cells
What do SCID & nude mice lack (T/B cells) ?
61
Cells & microenvironment
Adoptive
transfer
Flow cytometry
62
T cells : thymus
MHC restriction
Positive selection
63
MHCa
MHCaxb
Hematopoiesis
MHCb
APC
MHCa
MHCb
MHCaxb
64
Bone marrow chimera
Thymic non-lymphoid stroma
Bone marrow-derived APC
?
65
Positive selection : MHC restriction
66
T cell development
Gene
rearrangement
Cortex
Medulla
Positive selection : MHC restriction
Negative selection : Self tolerance
67
Negative selection: self tolerance
AIRE
(Autoimmune regulator)
Transcription factor
AIRE regulates the expression of ubiquitous self antigens & a wide variety
of tissue-restricted self Ag (e.g. pancreas, brain) at low levels in the thymus
APC
CD8T
DC
69
Natural
regulatory
T cells (Treg)
Negative
?
selection
Negative selection: self tolerance
Bone marrow-derived
Negative selection : clonal deletion & Treg
Ann Rev Immunol 30: 531, 2012
T cell development
AIRE medulary cells
Natural
Treg
The presence of
autoreactive lymphocytes
in periphery
T cell development
T cell subpopulations
T cells
ab TCR
CD4T
CD8T
gd TCR
1. Antigen specificity
2. Diversity
MHCII
MHCI
3. Immunological memory
4. Self tolerance
AgR
Innate
immunity
Pattern recognition
Germline-encoded receptors
Epitope recognition
Gene rearranged
receptors: TCR/BCR
Adaptive
immunity
B/T cells