From an artificial experimental system to normal immune systems

The transplantation system briefly described here has demonstrated that TE-induced tolerance to peripheral tissues operates in the presence of both non-tolerant and regulatory T cells with specificity to tissue antigens of the TE donor strain. Although direct evidence is still not available, these observations strongly suggest a role of TE in induction of regulatory T cell function. In turn, TE-selected regulatory T cells ensure peripheral tolerance of tissue-

specific antigens of the TE donor. The production of both aggressive and regulatory T cells by thymic selection in TE chimeras is explained on the basis of the established inefficiency of TE to mediate deletion of self reactive T cells. The regulatory activity generated in the thymus of allogeneic TE chimeras can be maintained in the periphery for long periods of time, even after decay of the initial pool of regulatory T cells.

These observations provided the basis for a strategy followed by the immune system to deal with potentially aggressive tissue-specific T cells produced throughout life, which is not based on their elimination or inactivation, but on their recruitment into the regulatory pool, thus progressively reinforcing peripheral tolerance. This strategy appears fully adapted to the T cell population dynamics in development.

A normal thymus is expected to delete (on hematopoietic APCs) most TE-selected regulatory T cells, such that their production and export must be predominantly restricted to the perinatal period, before full HC colonization.

A small number of TE-selected regulatory T cells produced early in ontogeny, can ensure the peripheral functional 'education' of all tissue-specific T

Education

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Regulatory T cell 1 *"

No 3

Education

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First wave of regulatory T cells

Seoond wavtr of regulatory T colls

MHC molecules

▼ , Ubiquitous peptide recognised by T cell No. 0.

^ ^ Y . Tissue-specilic peptides respectively (Bcognized by T cell No 1, 2 and 3

Figure 3 Diversification of the tissue-specific regulatory T cell pool and the corresponding 'repertoire spreading' of peptidic self markers by a chain reaction of peripheral RTE education. The chain is initiated by T cell No. 0, which is a regulatory T cell selected by TE, and, thus 1) specific for an ubiquitous peptide, and 2) the first to be produced and exported to the periphery.

cells, given that the whole T cell pool is postnataliy built up by accumulation of RTEs. This process explains the establishment, maintenance and renewal of the peripheral pool of self-specific regulatory activities. Thus, it accounts for a fundamental aspect of natural self tolerance: in spite of the life-long production of newly-formed T cells in the thymus, acquisition of tolerance is restricted to the perinatal period, such that a developmental shift from tolerance to immunity occurs in normal animals.

The prediction is that the 'regulatory' T cell repertoire progressively shifts from TE-specific towards tissue-specific, through the local recruitment of tissue-specific RTEs by TE-selected T cells recognizing ubiquitous peptides, that can prevent destruction of a variety of tissues.

The finding that functional recruitment of RTEs requires antigen recognition also explains why newly formed T cells with specificities towards nonself antigens differentiate as naive resting cells to recruit-ment-resistant PRMs. It follows that antigens introduced in adult life will induce conventional immune responses that are no longer submitted to regulation, providing the basis for the developmental shift from tolerance to immunity.

A similar process of 'education' was previously described in mice tolerized to minor histocompatibility antigens, after in vivo treatment with nonde-pleting anti-CD4 and anti-CD8 monoclonal antibodies. This process, designated 'infectious tolerance', was shown to operate on CD4 T cells of thymectomized mice, hence on nonrecent thymic emigrants. This experimental system failed, however, to tolerize to major histocompatibility antigens.

Available observations suggest a major role of regulatory T cells in the establishment and maintenance of natural tolerance in normal animals. Neonatal thymectomy induces T cell-mediated, organ-specific autoimmune diseases that can be prevented by transfers of normal adult CD4 T cells, suggesting the operation of thymus-selected regulatory cells during normal development. Normal adult rats and mice contain subsets of T cells that can induce autoimmune disease if transferred into immunodeficient recipients, but also harbor other T cell subsets which confer protection from this autoaggressive T cell activity. The repeated findings of 'spontaneous' autoimmune disease in interleukin- or T cell-deficient mice is also most compatible with dominant tolerance mechanisms. Finally, Lafaille and colleagues have recently shown that mice transgenic for an autoreactive tissue-specific TCR against myelin basic protein will only develop disease at high frequency if crossed into a RAG-1-deficient background; that is, in the complete absence of any other T or B cell population.

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