Chapter 10 Immunologic Tolerance General Features and Mechanisms T Lymphocyte Tolerance B Lymphocyte...

Chapter 10Chapter 10 Immunologic Immunologic ToleranceTolerance

General Features and Mechanisms

T Lymphocyte Tolerance

B Lymphocyte Tolerance

Tolerance induced by Foreign Protein Antigens

Homeostasis in the Immune System

Immunologic Tolerance—— an antigen induced specific unresponsivenessunresponsiveness

Tolerogens Immunogens

Self-tolerance Autoimmunity

Tolerance induced by foreign antigens

What is Immunologic Tolerance?

FailureFailure

General Features and Mechanisms

Immunologically specificImmunologically specific A result of antigen recognition by specific A result of antigen recognition by specific

lymphocyteslymphocytes

Neonate

Adult

Skin graft rejection + +_

Studies of graft rejection in inbred mice

Immunologically specific

a result of the recognition of antigens by specific lymphocytes

During lymphocyte maturation in the generative lymphoid organs, all lymphocytes pass through a stage in which encounter with Ag leads to tolerance

Strain A Strain A Strain A

General Features and Mechanisms

Immunologically specificImmunologically specific Central tolerance:Central tolerance:

induced in generative lymphoid organs immature self-reactive lymphocyte

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

Burnet: Clonal selection hypothesis

General Features and Mechanisms

Immunologically specificImmunologically specific Central tolerance:Central tolerance:

generative lymphoid organs immature self-reactive lymphocyte

Peripheral tolerance:Peripheral tolerance: peripheral sites mature self-reactive lymphocytes

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

Important for maitaining unresponsiveness to self antigens that are not expressed in the generative lymphoid organs.

Peripheral tolerance is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.

The principal mechanisms of lymphocyte tolerance

Deletion: apoptotic cell death

Anergy: functional inactivation without cell death

Treg

Central tolerance

Peripheral tolerance

Apoptosis

Immunologic Immunologic ToleranceTolerance

General Features and Mechanisms

T Lymphocyte Tolerance

B Lymphocyte Tolerance

Tolerance induced by Foreign Protein Antigens

Homeostasis in the Immune System

T Lymphocyte Tolerance

Central T Cell Tolerance Peripheral T cell Tolerance

Maturation of T cells in the thymus

Negative selection: Development of central tolerance

High affinity

High concentration

Self antigens expressed in the thymus

ubiquitous self-antigen: widely expressed in the body

tissue-specific antigenautoimmune regulator gene, AIRE

Natural Tregs arise in the thymus

T Lymphocyte Tolerance

Central T Cell Tolerance Peripheral T cell Tolerance

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsActivation induced cell death (AICD)Regulatory T LymphocytesFactors that determine the tolerogenicity of self antigens

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsAICDTregFactors that determine the tolerogenicity of self antigens

Sig2

(co-stimulation)

1975 Lafferty & Cunningham

T helper cells die when they see antigen unless rescued by co-stimulation(signal two) from APCs.

Two Signal model

co-stimulatory signal

Figure 8-20Gowth factor: IL-2

Anergy is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.

Figure 8-12CTLA-4/B7 initiate the inhibitory signal

Anergy may be induced if T cells use CTLA-4 to recognize costimulators on APCs

Question

Recognize the same B7 with CTLA-4 (inhibitory receptor)

Factors

?

?

Tolerance

Immune response

?

?T cells recognize B7 molecules

with CD28 (active receptor)

?T cells

?

?

T cells?

Making and breaking tolerance

The nature of tissue APCs is an important determinant of whether self-tolerance or autoimmunity develops.

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsAICDTregFactors that determine the tolerogenicity of self

antigens

Activation induced cell death

Repeated stimulation of T cells by persistent antigen results in death of the activated cells by a process of apoptosis

AICD is a form of apoptosis induced by signals from membrane death receptors

Fas-mediated activation-induced cell death

activation activation

The net effect is that the population of mature lymphocytes is depleted of antigen specific lymphocytes by repeated stimulation.

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsAICDRegulatory T Lymphocytes (Treg)Factors that determine the tolerogenicity of self antigens

Immunity 2009; 30: p626

Treg cell development

T cell-mediated suppression

Mechanisms of action of regulatory T cells

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsAICDRegulatory T Lymphocytes (Treg)Factors that determine the tolerogenicity of self antigens

Factors That Determine the Immunogenicity and Tolerogenicity of Protein

Factor Factors that favor stimulation of immune response

Factors that favor tolerance

Amount Optimal doses that vary for different antigens

High doses

Persistence Short-lived(eliminated by immune response)

Prolonged (AICD)

Portal of entry; location

Subcutaneous, intradermal; absence from generative organs

Intravenous, oral; presence in generative organs

Presence of adjuvants

Antigens with adjuvants: stimulate helper T cells

Antigens without adjuvants:

Properties of APCs

High levels of costimulators Low levels of costimulators and cytokines

Immunologic Immunologic ToleranceTolerance

General Features and Mechanisms

T Lymphocyte Tolerance

B Lymphocyte Tolerance

Tolerance induced by Foreign Protein Antigens

Homeostasis in the Immune System

B Lymphocyte Tolerance

Central B Cell Tolerance Peripheral B cell Tolerance

Checkpoints during B cell maturation and activation at which encounter self Ags may abort these process

B cell development in bone marrow

Central tolerance in B cells

• Immature B cells that recognize self antigens in the in the bone marrowbone marrow with high affinityhigh affinity are deleted or change their specificity.

• multivalent self antigens: cell membrane molecules 、 polymeric molecules

HEL transgenic

What is the result of self antigen recognition in generative lymphoid organ?

Down-regulation of antigen receptor expression

Change in receptor specificity (receptor editing)

B Lymphocyte Tolerance

Central B Cell Tolerance Peripheral B cell Tolerance

B7 CD28

T-B Collaboration

Peripheral tolerance in B cells

• Mature B cells that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive.

If anergic B cells do encounter any antigen-specific helper T cells, what

happened?

The B cells maybe killed by FasL on the T cells engaging Fas on the B cells.

头发 Hair脱发 alopecia

脑 Brain癫痫 seizures精神病 psychosis头痛 headache

脸 Face颊部红斑 malar rash盘状红斑 discoid rash

心 Heart心包炎 pericarditis心肌炎 myocarditis心内膜炎 endocarditis肺动脉高压 pulmonary hypertension

小肠 Intestines血管炎 vasculitis

手 Hands雷诺氏现象 Raynauds phenomenonJaccoud 关节病

关节 Joints关节炎 arthritis

肺 Lungs胸膜炎 pleurisy间质性肺炎 interstitial pneumonia

血液、血管 Blood & Vessels血管葱皮样改变 onion-skin like artery贫血 anemia血栓 thrombosis

肾 Kidneys蛋白尿 proteinuria管型 casts

足 Feet血管炎 vasculitis

systemic lupus erythematosus systemic lupus erythematosus 

蝶型红斑 （ Butterfly rash ）

Homogenous pattern

Peripheral pattern

Speckled pattern

• Normal individals do not produce autoantibodies against self protein antigens, and this may be due to deletion or tolerance of helper T lymphocytes even if functional B cells are present.

• Defects in the maintenance of T cell tolerance may result in autoantibody production

FeatureFeature T lymphocyteT lymphocyte B lymphocyteB lymphocyte

Principal sites Principal sites Thymus (cortex);peripheral

Bone marrow; peripheral

Tolerance-Tolerance-sensitive stage sensitive stage

CD4+CD8+ thymocyte Immature B lymphocytes

Stimuli for Stimuli for tolerance tolerance inductioninduction

Central: high-avidity recognition of Ag in thymus

Central: high-avidity recognition of multivalent Ag in bone marrow

Peripheral: Ag presentation by APCs lacking costimulators; repeated stimulation by self Ag

Peripheral: Ag recognition without T cell helper

Principal Principal mechanisms of mechanisms of

tolerancetolerance

Central tolerance: clonal deletion (apoptosis)

Central tolerance: clonal deletion (apoptosis), receptor editing

Peripheral tolerance:: anergy, AICD, suppression

Peripheral tolerance: block inblock in signal transduction (anergy); failure to enter FC

Immunologic Immunologic ToleranceTolerance

General Features and Mechanisms

T Lymphocyte Tolerance

B Lymphocyte Tolerance

Tolerance induced by Foreign Protein Antigens

Homeostasis in the Immune System

Factors That Determine the Immunogenicity and Tolerogenicity of Protein

Factor Factors that favor stimulation of immune response

Factors that favor tolerance

Amount Optimal doses that vary for different antigens

High doses

Persistence Short-lived(eliminated by immune response)

Prolonged (AICD)

Portal of entry; location

Subcutaneous, intradermal; absence from generative organs

Intravenous, oral; presence in generative organs

Presence of adjuvants

Antigens with adjuvants: stimulate helper T cells

Antigens without adjuvants:

Properties of APCs

High levels of costimulators Low levels of costimulators and cytokines

Immunologic Immunologic ToleranceTolerance

General Features and Mechanisms

T Lymphocyte Tolerance

B Lymphocyte Tolerance

Tolerance induced by Foreign Protein Antigens

Homeostasis in the Immune System

Termination of normal immune response

Mechanisms of the decline of normal immune response (homeostasis)

CTLA-4 、 Fas 、 FasL

24 h

B7

CD28

Ag

TCR

B7

CTLA-4

Active signal

I T I MI TAM

Inhibitorysignal

T cell

Antibody feedback

The repertoire for TCR and BCR (Ab)

Ab1Ab2AgAg

Ab3

Ab1

Ab2

Niels Jerne: Network hypothesis

thresholdthreshold

Idiotype and anti-idiotypic

Reach a steady state at which the immune system is at homeostasis

Summary

What is immunologic tolerance?Central and peripheral toleranceTolerance in T and B cellsHomeostasis

Tolerance—— an antigen induced specific unresponsivenessunresponsiveness

Tolerogens Immunogens

Self-tolerance Autoimmunity

Tolerance induced by foreign antigens

What is Immunologic Tolerance?

FeatureFeature T lymphocyteT lymphocyte B lymphocyteB lymphocyte

Principal sites Principal sites Thymus (cortex);peripheral

Bone marrow; peripheral

Tolerance-Tolerance-sensitive stage sensitive stage

CD4+CD8+ thymocyte Immature B lymphocytes

Stimuli for Stimuli for tolerance tolerance inductioninduction

Central: high-avidity recognition of Ag in thymus

Central: high-avidity recognition of multivalent Ag in bone marrow

Peripheral: Ag presentation by APCs lacking costimulators; repeated stimulation by self Ag

Peripheral: Ag recognition without T cell helper

Principal Principal mechanisms of mechanisms of

tolerancetolerance

Central tolerance: clonal deletion (apoptosis)

Central tolerance: clonal deletion (apoptosis), receptor editing

Peripheral tolerance:: anergy, AICD, suppression

Peripheral tolerance: block inblock in signal transduction (anergy); failure to enter FC

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