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Peripheral tolerance and Immunoregulation. Dr. C. Piccirillo Canada Research Chair Department of Microbiology & Immunology McGill University MIMM-414A Lecture 1- Oct. 20, 2006 Why T cell regulation?

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Peripheral tolerance and Immunoregulation.

Dr. C. Piccirillo

Canada Research Chair

Department of Microbiology & Immunology

McGill University

MIMM-414A

Lecture 1- Oct. 20, 2006


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Why T cell regulation?

How does the immune system prevent self-reactivity while maintaining reactivity to invaders/non-self?

T cell regulation in the absence

of regulatory T cells?

  • Suppression of autoreactive T cells

  • Control immunity to enteric bacteria

  • Limit histopathology


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Self/non-self discrimination

  • Turn of the 20th century 1901: Ehrlich and Morgenroth

    • Immunized goats with RBC from another goat to conclude that host immune responses respond to foreign antigens.

    • They coined the Latin phrase: horror autoxicus

    • Why did the goats develop autoAb to their own RBC?

  • 1938- Traub induced tolerance by injecting LCMV in utero into mice producing an infection that was long-lived in life.

  • 1949- Macfarlane Burnet: postulated that the age of the animal at the time of the first encounter with antigen was the critical determinant in the induction of tolerance.

  • 1953: Medawar induced immune tolerance to skin allografts in mice by neonatal injection of allogeneic cells.

  • Prevention or failure to mount response to self-components?


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Immunological tolerance

A state of functional unresponsiveness for a particular antigen.

May occur in the context of a non-inflammatory immune response.

Tolerance is an active process.


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Central tolerance largely controls self / non-self discrimination.

  • Thymic deletional processes are inefficient.

    • Moderate-high affinity TCR/pMHC interactions --> clonal deletion

    • Low-moderate TCR/pMHC interactions -> selection

    • No interaction- neglect and death

    • BMDC involved in clonal deletion (cortico-medullary junction)

    • T cell maturational state is important (nature,site and how)

    • Role of AIRE (AutoImmune Regulator)

  • Autoreactive T cells leave thymus and exist in periphery.

  • Absence of disease suggests mechanism of active suppression.


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Multiple mechanisms ensure peripheral T cell tolerance.

  • Ignorance: anatomy, lymphatics, Ag crypticity, privilege

  • Deletion : cross-presentation of Ag by BMDC results in death (eg;CD8+)

  • Anergy: Insufficient co-stimulation on self-tissues

  • Clonal exhaustion: CD8+ T cells in chronic viral infections

  • Immune deviation: shift from inflammatory to anti-inflammatory

    cytokine production (eg; Th1-Th2).

  • Activation-induced cell death (AICD): Fas/FasL (IL-2) = Death

    Peripheral tolerance is an adaptable process.


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Tolerance to Self Antigen

  • Antigen sequestration (lens of eye, spermatozoa)

  • Low MHC expression (i.e. hepatocytes)

Immune Response to Foreign Antigens

  • Influence of Antigen

Dose (low zone, high zone), timing/duration of exposure, routes, nature of antigen, protein > CHO >> lipids, presence of adjuvants

  • Influence of Antibody

feedback inhibition (IgG inhibits IgM), differential antigen binding affinity

  • Factors favoring tolerance

  • Age, neurological and endocrine factors, Nutritional status, MHC

  • Haplotypes


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Acquired Tolerance

  • In many cases, experimental unresponsiveness may be mediated by suppressor (T) cells, which actively prevent an immune response.

  • Original experiments of Gershon and Kondo (1970) showed that T cells were required for tolerance induction. Moreover, T cells from tolerant mice suppressed B cells from normal mice.

  • Active suppression by T cells also seen in some responses under Ir gene control and in the regulation of IgE responses (Tada).

  • Suppression commonly induced by systemic administration of antigen-coupled to self cells; route of injection is important (i.v. favors; intradermal gives contact sensitization).

  • Suppressor T cells produce factors. These factors may act directly on T/B targets.

  • Can be adaptively transferred.


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Infamous Suppressor T cells

  • Suppressor or Regulatory lymphocytes

    • Patrol periphery, silencing self-reactive T cells and maintain tolerance.

  • 1970’s-early 80’s

  • Gershon, Kondo, Tada…..

  • Taboo of T “suppressor” cells

    • CD8+

    • Complex regulatory networks mapping to I-J (within the MHC)

    • Molecular cloning of TCR and MHC disappointed in T cell hybridomas secreting “suppressor factors”

    • No identifiable cell surface marker

    • No clone or cell lines with suppressor activity

    • No antigen specific suppressor factor gene identified

    • Transient phenotype


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The reincarnation of the suppressor T cell

More questions than answers.

Questions

?

n

Number of publications

*

1

1995 - Present

Answers


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A network of CD4+ regulatory T cells

control immune reponses.

Thymic CD4+ T cell pool

Thymically-derived

naturally-occurring

CD4+CD25+ Treg cells

(nTreg )

Peripherally-induced

CD4+ Treg cells

( iTreg )

Foxp3+

GITR+

CTLA-4+

CD25+

TCR

TCR

+ Peripheral

differentiation

signals

CD25

GITR

CTLA-4

Foxp3

CD25 +/-

GITR +/-

CTLA-4 +/-

Foxp3 +/-

APC

_

_

Activated

Effector

T cell

Autoimmunity

Transplantation

Tumor Immunity

Infectious disease

Piccirillo et al. Trends in Immunol. 2004.


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