Lymphocyte Selection and Tolerance

Chander Raman2004

Lecture Focus:

• Lymphocyte Selection: Central Tolerance• T-cell selection• B-cell selection

• Peripheral Tolerance • Peripheral control of autoreactivity.

• Breakdown of tolerance• Autoimmune diseases

• Restoration of tolerance• Treatment of autoimmune diseases

Tolerance: Inability to respond to antigen stimulation OR Immunological unresponsiveness.

Why do we need tolerance?

-Initial T-cell receptor rearrangement or B-cell receptor rearrangement leads to generation of repertoire that has the potential to recognize all antigens –

DOES NOT DISCRIMINATE BETWEEN SELF-REACTIVITY AND REACTIVITY TO FOREIGN ANTIGENS

Tolerance:

• Central tolerance• Negative selection of immature lymphocytes by clonal deletion of self reactive clones during development.

• T cells – thymus• B cells – bone marrow

Clonal deletion occurs by induction of programmed cell death or apoptosis

Death by Neglect

Negative Selection

T-Cell Selection - Overview

Double Negative

Double PositiveCD4+CD8+

Single PositiveCD4+ orCD8+(Positive selection based on MHC reactivity)

(Negative Selection)

(Positive selection for ability to recognize antigen)

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Death by Neglect

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Evidence for Requirement for Central Tolerance

AIRE (autoimmune regulator) Transcription Factor –”Master” Regulator of Ectopic Expression of Peripheral Tissue- Restricted Antigens in stromal cells of the thymic Medulla.

•Originally identified as a human autosomal recessive disorder known as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

• AIRE-/- mice exhibit wide spread organ-specific autoimmunity, such as ovary, retina testis, stomach. (Anderson et al, Science)

AIRE-Deficient Mice

Normal Mice

Loss of Thymic Selection lead to Autoimmunity

Autoantibodies to different organs shown in GREEN in AIRE-deficient mice

AIRE allows for the expression of antigens to which T-cells are negatively selected.

B-Cell Development

Sensitive to Negative Selection – Central Tolerance

Binding to self molecules in the bone marrow can lead to the deletion or inactivation of immature B cells.

B-Cell Selection in the Bone Marrow

Factors That Regulate Central Tolerance

• Most Important – Strength of Signals initiated by antigen receptor– Intracellular signal strength is dependent on:

• Avidity of interaction of between antigen and antigen receptor

• Affinity of interaction between antigen and antigen receptor

• Co-stimulatory signals that enhance signal strength (CD28)

• Signals that attenuate signals strength – Inhibitory receptors (CD5)

Signal Strength

Survival

Death

Negative selectionPositive selectionDeath by Neglect

Co-stimulation

Inhibition (attenuation)

Peripheral Tolerance• Not all self-reactive T or B cells are deleted

during development. Reasons include:– Need for a peripheral repertoire that will protect

from pathogens– Peripheral tissue specific antigens not expressed

in the thymus.– Expression of neo-antigens occurring as a result

of tissue damage.– Expression of specific endopeptidases that modify

peptides in thymus.– Positive selection of specificities that exhibit weak

self-reactivity but with the propensity for pathogenic autoreactivity.

Control of autoreactive T cells in the periphery is termed Peripheral Tolerance

Peripheral Tolerance

Peripheral control of autoreactivity

• Peripheral Tolerance:– Clonal deletion, clonal anergy or clonal

ignorance of mature self-reactive T and mature or transitional B cells.

– Regulated by:• Co-stimulatory molecules (signal 2)• Cytokines (signal 3)• Inhibitory molecules• T-regulatory cells (Tr), T-suppressor cells (Ts)• Dendritic cells.

Anergyand/or

Apoptosis

Maloy and Powrie, Nature Immunol. 2:816

T Regulatory Cells (Tr)

CD4+

CD25+

T suppressor cells and Inhibitory Molecules

Feinberg & Silvestri, Nature Immunol, 3:215

Tolerance Induction by Dendritic Cells

Lutz and Schuler, Trends Immunol: 23:9

Immunity vs Tolerance in Peripheral B Cells

Breakdown of tolerance Autoimmune

diseases

Venn Diagram: Requirements for the Development of Autoimmune Disease

Focus on AutoimmunityNature Immunology, Sept 2001 (Vol 2)www.nature.com/ni

Development of Autoimmunity

Autoimmune Diseases

• Organ specific autoimmune diseases:– Immune response directed to a specific organ

leading to cellular damage and organ destruction

• Diabetes – Cell mediated immune response to pancreatic islet beta cells.

• Goodpasture’s syndrome – Antibody to basement membrane of kidney glomeruli.

• Graves disease – Stimulating antibody to thyroid stimulating hormone receptor (TSHr)

Autoimmune Diseases

• Systemic autoimmune diseases:– Immune response to wide variety of antigens involving

several organs and tissues. Often involves both cell-mediated and humoral.

• Systemic lupus erythematosus (SLE) – Primary antibody response to DNA and nucleoproteins and progressive development of antibodies to other tissues.

• Rheumatoid arthritis (RA) – IgM antibodies to Fc portion of IgG.

• Multiple sclerosis (MS) – T cell response to myelin basic protein

Organ Specific and Systemic Autoimmune Diseases in Human

Hypothesis for the Development of Type 1 Diabetes

Systemic Lupus Erythematosus

- Genetic Predisposition- MHC genes – eg. HLA DR4 in Diabetes- Other susceptibility genes

- Sex Differences

Susceptibility to Autoimmune Diseases

Contribution of Susceptibility Gene Alleles to Development of Autoimmunity

Therapeutic Intervention

- Conventional therapeutic approaches- Anti-inflammatories, immunosuppressive drugs, Cytotoxic drugs

- New therapies- TNFr (EMBREL – etanerecept)- anti-CD20 (depletes B-cells – treatment of SLE)

- Experimental/New approaches- TNF receptor family agonists/antagonists

- Blys/BlysR(s) (Inhibition of activation and differentiation)- TRAIL/TRAILR(s) (Apoptosis inducing)

Ware, Nature. 404:949

Decoy Receptors in Regulation of Lymphocyte Activation and Autoimmunity

Soluble Receptor

Agonist or antagonist antibody

Pharmacological Inhibitors

Decoy Receptors In Treatment of Autoimmune Diseases