Ch8
The development of lymphocytes
Immune system
Design for living
Boundary
Self/non-self recognition
Ags……….
Innate
immunity
Germline-encoded receptors
Adaptive
immunity
Gene rearranged
receptors: TCR/BCR
Lymphopoiesis
B/T cell development
AgR
Cells
Microenvironment
Adaptive immunity
1. Antigen specificity
2. Diversity
3. Immunological memory
4. Self tolerance
Aim of development
1. Production of AgR
2. Functional Ag recognition
Self Ag?
MHC-restricted?
Hematopoiesis
Central lymphoid organs
Microenvironment
Commitment
Productive rearrangement?
Cell survival & death
One cell
one AgR
Clone
Fate
B-cell development
T-cell development
Positive & negative selection
B cell development
Microenvironment
Die
Survive
Transcription factors
Proteins, receptors
The dependence on bone marrow stromal cells
Adhesion
molecules
Cell-cell
interaction
Early stages
Growth
factors
B cell commitment
Proliferation
(SDF-1)
Constitutive production
Ig gene rearrangement
Heavy chain
One receptor
on one cell
Allelic exclusion
Protein-regulated gene rearrangement
Protein-regulated gene rearrangement
Cell survival or death
Self-reactivity
Fate
The presence of autoreactive lymphocytes in periphery
Receptor editing
7-8
Fig. 7-23
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, ..)
T cell development
Self MHC restriction
Self tolerance
Cells
Microenvironment
Affinity
Thymus
Epithelial cell
network:
thymic stroma
The importance of thymus
in T-cell development
Thymectomy
DiGeorge’s syndrome
Defective repairing system
Genetic defect of a gene coding for
transcription factor Wnt required for
terminal differentiation of
cortical epithelial cells
Cells & microenvironment
Flow cytometry
T cell
development
gdTCR
T cell subsets in central and peripheral organs
Flow cytometry: immunostaining
Normal
T cell commitment
R: Notch 1
Microenvironment
abTCR
or
gdTCR ?
b
Developmental
control of
gd T cells
Ordered sequence
abTCR
or
gdTCR ?
b
Cells
Repeated rearrangements can rescue nonproductive VaJa joins
a gene rearrangement induces d gene deletion
After TCR rearrangement
Microenvironment
MHC restriction
Self tolerance
Positive selection :
MHC restriction
Cortex
MHCI-CD8
MHCII-CD4
Positive selection
(T cell precursor)
T cells : thymus
MHC restriction
Ag encounter in periphery
Bone marrow-derived
DC/macrophages
Bone marrow chimera
Thymic non-lymphoid stroma
Bone marrow-derived APC
Negative selection: self tolerance
Bone marrow-derived
Negative selection : Self tolerance
AIRE expression on thymic medulary cells
Medulary epithelial marker MTS10
Self antigen
(encoded by the
host’s genome)
AIRE
(Autoimmune regulator)
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
Microenvironment
MHC restriction
Self tolerance
affinity
T cell development
AIRE medulary cells
Central tolerance
The presence of
autoreactive lymphocytes
in periphery
The development of lymphocytes
重要性
細胞
地點
時間
如何運作
結果
特性
比較異同
Adaptive immunity
1. Antigen specificity
2. Diversity
3. Immunological memory
4. Self tolerance
Techniques
Adoptive transfer
Techniques
Hormone
Transgenic mice
Fertilized egg
Transgene
Hybridoma
TCR transgene
Knock-out
mice
Knock-out
mice
黑
白
Knock-out
mice
Knock-in
mice
Lethal effect
Positive selection
MHC II restriction:
Interaction of CD4 with MHCII
Host
Inducible
knock-out
mice
Tissue specificity
Cre/lox system
Enzyme
(recombinase)
in other tissues