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? 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
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?
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.
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.
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.
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
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.
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
The reincarnation of the suppressor T cell More questions than answers. Questions ? n Number of publications * 1 1995 - Present Answers
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.