Germline-encoded receptors

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