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Innate immunity. Ags………. Germline-encoded receptors. Pattern recognition. Adaptive immunity. Gene rearranged receptors: TCR/BCR. B/T cells. Epitope recognition. ?. Ags………. Foreign Ag Self Ag. 自我耐受性. Self tolerance. Ag recognition. Gene rearranged receptors. Structure. - PowerPoint PPT Presentation
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Germline-encoded receptors
Gene rearranged receptors: TCR/BCR
Ags………. Innate immunity
Adaptive immunity
B/T cells
Pattern recognition
Epitope recognition
?Ags……….
Foreign AgSelf Ag
Ag recognition
Self tolerance
自我耐受性
BCR/TCR:Ag recognition
Fig. 5.1
MHC-restriction
Extracellular Ag
Intracellular Ag
Structure
Gene rearranged receptors
Heavy chain (H)
Light chain (L)
Variable region
Innate immunity
Adaptive immunity
Hematopoiesis
Central lymphoid organs
Microenvironment
Cell survival & death
Commitment
Productive rearrangement?
2
Clonal selection Immune diversity
Antigenspecificity Diversity
Memory
Gene rearrangement
of TCR/BCR
Adaptive immunity
Bone marrow 骨髓
Note: low frequency of Ag-specific cellsClone
Peripheral tolerance
Central tolerance
Thymus 胸腺
Adaptive immunity
1. Antigen specificity
2. Diversity
3. Immunological memory
4. Self tolerance
Four characteristics
Heavy chain
Co-dominant
Allelic exclusion
One receptor on one cell
Cell survival or death Allelic exclusion
Ig gene rearrangement
Stromal cells Adhesion molecules Chemokines & RCytokines & R
BM microenvironment
The dependence on bone marrow stromal cells
Early stages
SDF-1
Cell-cell interaction
Migration
Self-reactivity
Fate
The presence of autoreactive lymphocytes in periphery
Microenvironment: thymus
Site of cell destruction
Epithelial cell network: thymic stroma
T cell developme
ntTCR
TCR genes
TCR
TCRor
?
gene rearrangement induces gene deletion
Positive selection : MHC restriction
MHCI-CD8
MHCII-CD4
Negative selection: self tolerance
Bone marrow-derived
AIRE expression on thymic medulary cells(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
Negative selection : Self Ag presentation
Natural regulatory T cells (Treg)
Negative selection : clonal deletion & Treg
Ann Rev Immunol 30: 531, 2012
T cell development
AIRE medulary cells
The presence of autoreactive lymphocytes
in periphery
Natural Treg
CD4T
TCR TCR
T cells
CD8T
MHC-II MHC-I
T cell subpopulations
T cell development
Induction of adaptive immunity
Differentiation of Th
Cytokines
Cell-mediated immunity
Humoral immunity
Immunological memory
Adaptive immunity
Ag Innate Adaptive
Extracellular Phagocytes B cells
Intracellular NK CD8 Tc cells(Altered self)
Immunity & Ag location
Cytotoxicity
CD4 Th
Humoral response
Cell-mediated immunity (CMI)
Th1
Th2
Phagocytes
Antigen-Presenting Cells (APC)
B/T cells
Lymphocyte activationClonal selectionHumoral Imm/CMIMemory
Inflammatory site
Inflammation
Inflammatorysite
Lymph node
Induction of adaptive immunity
Dendritic cells (DC)
Lymph node distribution in the body
Lymph node
Induction of adaptive immunity
Differentiation of CD4 Th
Cytokines
Cell-mediated immunity
Humoral immunity
Immunological memory
Immune effector
function
Naïve, activated, effector
Humoral immunityCell-mediated immunity (CMI)
Act
ivat
ion
Eff
ecto
r
Naïve T cell activation in peripheral lymphoid organs
Three signals in naïve T cell activation
PrimingThe activation and differentiation of naïve T cells
Costimulation
CD4 T cell activation
IL2 production
Clonal expansion
Signal 1+2
IL2R
CD4 T cell differentiation
CMI: CD8 T Humoral response
Th17
Promote local inflammation
Treg
Signal 3: cytokine
TH17
Recruitment of neutrophils
Activation of macrophages
Antimicrobial peptides
Ubiquitous expression of IL17R on tissue cells: fibroblasts, epithelial cells, keratinocytes, etc.
Cytokines: G-CSF, GM-CSF
Chemokines: CXCL8, CXCL2
Proinflammatory cytokine
Antimicrobial peptides PhagocytosisInflammed site
Signal 1+2
BM: 10 /dayDuring acute inflammation: 10 fold increase of production
10
Cytokines made in the later stages of infection
Differentiation of Th1 or Th2(polarization)
IL12 – Th1 IL4 – Th2
Intracellular infection Extracellular infection
Adaptive Treg
TH17
Rapid response to
infectionPreventing anti-selfresponse
Inhibition of proliferation & differentiation
TH17
Limiting immunopathology
Peripheral tolerance
Regulation among CD4 T subsets
Cytokine pattern of the dominant response
Inhibition of early Th17 response
Induction of adaptive immunity
Differentiation of Th
Cytokines
Cell-mediated immunity
Humoral immunity
Immunological memory
Immune effector
function
Effector response
Effector T cells
Membrane effector molecule
CMI: Macrophages activated by Th1
APC activation
Induction of adaptive immunity
Differentiation of Th
Cytokines
Cell-mediated immunity
Humoral immunity
Immunological memory
Immune effector
function
Effector response
Effector Th2 cells
Humoral immunity:B cell response
B cells as APC
CD4 T help in B cell differentiation
51
Induction of adaptive immunity
Differentiation of Th
Cytokines
Cell-mediated immunity
Humoral immunity
Immunological memory
Immune effector
function
Adaptiveimmunity
Ab:Affinitymaturation
AgHighly sensitive to
small amount of Ag
CD4 Th2 in B cell differentiation
54
Variable region
Ab: class switching
Protective immunity & time
Apoptosis of effectors
Memory cells:long-lived