The development of

lymphocytes

Ch

8

Immune system Design for living

Boundary

Self/non-self recognition

Germline-encoded receptors

Gene rearranged receptors: TCR/BCR

Ags………. Innate immunity

Adaptive immunity

Lymphopoiesis

B/T cell development

CellsMicroenvironment

AgR

1. Antigen specificity

2. Diversity

3. Immunological memory

4. Self tolerance

Adaptive immunity

MHC-restricted?

Self Ag?

Aim of development

1. Production of AgR2. Functional Ag recognition

Hematopoiesis

Central lymphoid organs

Microenvironment

Cell survival & death

Commitment

Productive rearrangement?

One cell

one AgR

CloneFate

B-cell development

T-cell development

Positive & negative selection

B cell development

Die

SurviveMicroenvironment

Transcription factors

Proteins, receptors

The dependence on bone marrow stromal cells

Early stages

Proliferation

(SDF-1)

Constitutive production

B cell commitmentCell-cell

interaction

Growthfactors

Adhesion molecules

Ig gene rearrangement

Allelic exclusion

One receptor on one cell

Heavy chain

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

Stromal cell-dependent (Spatial regulation)

Temporal regulation of protein expression

Proteins:

receptors, cytokines, TS factors, recombinase, ..)

B-cell development

B cell commitmentBCR rearrangementCell survival & death (BCR, self tolerance)

T

T cell development

Self MHC restriction

Self tolerance

CellsMicroenvironment

Affinity

Epithelial cell network: thymic stroma

Thymus

The importance of thymus in T-cell development

Genetic defect of a gene coding for transcription factor Wnt required for

terminal differentiation of cortical epithelial cells

Defective repairing system

ThymectomyDiGeorge’s syndrome

Cells & microenvironment

Flow cytometry

T cell development

TCR

T cell subsets in central and peripheral organs

Flow cytometry: immunostaining

Normal

T cell commitmentR: Notch 1

Microenvironment

TCR

TCRor

?

Developmental control of T cells

Ordered sequence

TCR

TCRor

?

Repeated rearrangements can rescue nonproductive VJ joins

Cells

gene rearrangement induces gene deletion

MHC restriction

Self tolerance

After TCR rearrangement

Microenvironment

Positive selection : MHC restriction

MHCI-CD8

Cortex

MHCII-CD4

T cells : thymusMHC restriction

Positive selection

(T cell precursor)

Ag encounter in periphery

DC/macrophagesBone marrow-derived

Bone marrow-derived APC

Thymic non-lymphoid stroma

Bone marrow chimera

Negative selection: self tolerance

Bone marrow-derived

AIRE expression on thymic medulary cells

AIRE(Autoimmune regulator)

Medulary epithelial marker MTS10

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

Self antigen

(encoded by the host’s genome)

Negative selection : Self tolerance

MHC restriction

Self tolerance

Microenvironment

affinity

T cell development

AIRE medulary cells

The presence of autoreactive lymphocytes

in periphery

Central tolerance

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

1. Antigen specificity

2. Diversity

3. Immunological memory

4. Self tolerance

Adaptive immunity

Adoptive transfer

Techniques

Transgenic mice

Transgene

Hormone

Fertilized egg

Techniques

Hybridoma

TCR transgene

Knock-out mice

Knock-out mice

Knock-in mice

黑

白

Lethal effect

Knock-out mice

Positive selection

MHC II restriction:Interaction of CD4 with MHCII

Host

Cre/lox system

Enzyme(recombinase)

Inducible knock-out

miceTissue specificity

in other tissues