Don Mason

A very high level of crossreactivity is an essential feature of the T-cell receptor

Abstract It is commonly accepted that a high level of antigen specificity is a feature of T-cell activation. However, here, Don Mason argues that a comprehensive response to foreign antigens requires that T cells are widely crossreactive, such that one cell reacts productively with approximately 10 6 different MHC-associated minimal peptide epitopes.

Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro.

CD4+CD25+ T cells in mice and rats are capable of transferring protection against organ‐specific autoimmune disease and colitis and suppressing the proliferation of other T cells after polyclonal stimulation in vitro. Here we describe the existence in humans of CD4+CD25+ T cells with the same in vitro characteristics. CD4+CD8–CD25+ T cells are present in both the thymus and peripheral blood of humans (∼ 10 % of CD4+CD8– T cells), proliferate poorly in response to mitogenic stimulation and suppress the proliferation of CD4+CD25– cells in co‐culture. This suppression requires cell contact and can be overcome by the addition of exogenous IL‐2. CD4+CD25+ cells from thymus and blood were poor producers of IL‐2 and IFN‐γ, and suppressed the levels of these cytokines produced by CD4+CD25– cells. However, CD4+CD25+ PBL produced higher levels of IL‐4 and similar amounts of IL‐10 as CD4+CD25– cells. Regulatory CD4+CD25+ T cells have an activated phenotype in the thymus with expression of CTLA‐4 and CD122 (IL‐2Rβ). The fact that CD4+CD25+ regulatory T cells are present with a similar frequency in the thymus of humans, ratsand mice, suggests that the role of these cells in the maintenance of immunological tolerance is an evolutionarily conserved mechanism.

CD25 Is a Marker for CD4+ Thymocytes That Prevent Autoimmune Diabetes in Rats, But Peripheral T Cells with This Function Are Found in Both CD25+ and CD25− Subpopulations

Previously we have shown that autoimmune diabetes, induced in rats by a protocol of adult thymectomy and split-dose gamma irradiation, can be prevented by the transfer of a subset of CD4+ T cells with a memory phenotype (CD45RC−), as well as by CD4+CD8− thymocytes, from syngeneic donors. Further studies now reveal that in the thymus the regulatory cells are observed in the CD25+ subset of CD4+CD8− cells, whereas transfer of the corresponding CD25− thymocyte subset leads to acceleration of disease onset in prediabetic recipients. However, in the periphery, not all regulatory T cells were found to be CD25+. In thoracic duct lymph, cells that could prevent diabetes were found in both CD25− and CD25+ subsets of CD4+CD45RC− cells. Further, CD25− regulatory T cells were also present within the CD4+CD45RC− cell subset from spleen and lymph nodes, but were effective in preventing diabetes only after the removal of CD25− recent thymic emigrants. Phenotypic analysis of human thymocytes showed the presence of CD25+ cells in the same proportions as in rat thymus. The possible developmental relationship between CD25+ and CD25− regulatory T cells is discussed.

Control of immune pathology by regulatory T cells.

There is now compelling evidence that immune responses for both foreign and self antigens are downregulated by T cells that are specialised for this function; these are known as regulatory T (T reg) cells. This review describes progress in the characterisation of the T reg cells that mediate both mucosal tolerance and tolerance to self antigens. The recent work on the antigen specificity, generation and mode of action of T reg cells is also reviewed.

Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease.

Glucocorticoids that are released from the adrenal glands in response to stress can have profound effects on the immune system. Here, Don Mason illustrates how genetic variation in the magnitude of such a response can determine susceptibility to an experimental autoimmune disease in rats and discusses the implications for susceptibility to inflammatory diseases in humans. He also addresses the possible long-term effects of glucocorticoids on the balance between the cell-mediated and the humoral aspects of immunity and how this balance may influence the temporal development of an immune reaction.

The third function of the thymus

Nonresponsiveness of mammalian T cells to self-antigens is not totally accounted for in terms of clonal deletion, T-cell anergy and T-cell ignorance: studies have shown that the T-cell repertoire of healthy individuals contains cells with the potential to cause autoimmune disease. This article describes a T-cell-mediated mechanism that prevents the realization of this potential and indicates how its failure can lead to the development of autoimmunity.

Sequence of rat interleukin 2 and anomalous binding of a mouse interleukin 2 cDNA probe to rat MHC class II-associated invariant chain mRNA

We now report the isolation and sequence of a rat IL-2 cDNA clone and the characterization of a cross-reaction to rat class II major histocompatibility complex (MHC)-associated invariant chain mRNA observed when using a mouse IL-2 cDNA probe to analyze rat mRNA

Some quantitative aspects of T-cell repertoire selection: the requirement for regulatory T cells.

Summary: How the adaptive immune system achieves self–non‐self discrimination is not well understood, and in this article consideration is given to some of the quantitative aspects of this problem. In particular, the modification of the T‐cell repertoire as a result of clonotypic deletion in the thymic cortex is discussed and shown to make a major contribution to the achievement of self‐tolerance. An evaluation is also made of the benefit of MHC restriction in preventing clonal deletion in MHC heterozygotes from being more profound than it is in homozygotes, despite the approximately twofold increase in the presentation of self‐peptides in the thymus in heterozygotes. The effect that receptor editing may have on the efficiency of positive selection is estimated. Finally, the conclusions from these considerations are used to suggest why a subset of T cells, the regulatory T cells, are required to control immune responses to certain self‐antigens. The potential value of regulatory T cells to the control of inflammation induced by pathogens is also briefly discussed.

Induction of resistance to active experimental allergic encephalomyelitis by myelin basic protein-specific Th2 cell lines generated in the presence of glucocorticoids and IL-4.

We have produced T cell lines with a Th2 phenotype in the presence of IL‐4 and the glucocorticoid dexamethasone (DEX). IL‐4 and DEX together were more effective in inducing a Th2 response than IL‐4 alone. Myelin basic protein (MBP)‐specific Th2 lines were obtained and their ability to induce experimental allergic encephalomyelitis (EAE) was studied. Lines treated with IL‐4 and DEX did not transfer passive EAE and did not induce cellular infiltration into the central nervous system as opposed to the encephalitogenic Th1 lines. Lines treated with IL‐4 and DEX did not protect animals from the effect of encephalitogenic Th1 lines when the two were injected together. However, a high proportion of animals injected with IL‐4 + DEX‐treated lines became refractory to the development of EAE after immunization with MBP; that is, it was possible to induce resistance to active EAE without prior episodes of disease. Interestingly, animals injected with T cell lines had accelerated antibody responses against MBP and the predominant isotype was dependent on the cytokines synthesized by the T cell line injected. There was not evidence that the resistance to active EAE was due to anergy of MBP‐reactive cells or the action of CD8+ cells. Our data suggest that MBP‐specific T cell lines prevent the induction of disease by deviating the reactivity to MBP from a cellmediated to a humoral one and not merely from a Th1 to a Th2 response.

T-cell subsets in autoimmunity

The demonstration that functionally different T-cell subsets can be defined by the isoforms of the leukocyte-common antigen, CD45, that they express, has prompted studies on the roles of these subsets in autoimmunity. The results have led to the identification of a particular subset of CD4+ T cells that have the ability to inhibit autoimmune disease. Further, it has been shown that diabetes in the B-B rat can be transferred by in vitro activation of T cells by Staphylococcal enterotoxin suggesting that superantigens may play a role in the pathogenesis of this disease. However, in this system too, it appears that a subset of T cells can inhibit the induction of autoaggressive cells. In other experimental autoimmune diseases there is evidence that CD8+ T cells can be protective and that these cells may mediate this protection by the synthesis of transforming growth factor-beta.