Central Tolerance in T Cells

During their maturation in the thymus, many immature T cells that recognize antigens with high avidity are deleted and some of the surviving cells in the CD4+ lineage develop into regulatory T cells (Fig. 14-2). The process of deletion, or negative selection, of T lymphocytes was described in Chapter 8, when the maturation of T cells in the thymus was discussed. This process affects both class I and class II MHC-restricted T cells and is therefore important for tolerance in both CD8+ and CD4+ lymphocyte populations. Negative selection of thymocytes is responsible for the fact that the repertoire of mature T cells that leave the thymus and populate peripheral lym-phoid tissues is unresponsive to the self antigens that are present in the thymus. The two main factors that determine if a particular self antigen will induce negative selection of self-reactive thymocytes are the presence of that antigen in the thymus, either by local expression or delivery by the blood, and the affinity of the thymocyte T cell receptors (TCRs) that recognize the antigen. Thus, the important questions that are relevant to negative selection are what self antigens are present in the thymus and how are immature T cells that recognize these antigens killed.

Self proteins are processed and presented in association with MHC molecules on thymic antigen-presenting cells (APCs). The antigens that are present in the thymus include many circulating and cell-associated proteins that are widely distributed in tissues. The thymus also has an unusual mechanism for expressing protein antigens that are typically present only in certain peripheral tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire. Some of these peripheral tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein. Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune polyendocrine syndrome (APS). This group of diseases is characterized by antibody-and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets. A mouse model of APS has been developed by knockout of the AIRE gene, and it recapitulates many of the features of the human disease. Studies with mice have shown that several proteins that are produced in peripheral organs (such as pancreatic insulin) are also normally expressed at low levels in thymic medullary epithelial cells, and immature T cells that recognize these antigens are deleted in the thymus. In the absence of functional AIRE (as in the patients and knockout mice) these antigens are not displayed in the thymus, and T cells specific for the antigens escape deletion, mature, and enter the periphery, where they attack the target tissues in which the antigens are expressed independent of AIRE. The AIRE protein may function as a transcription factor to promote the expression of selected tissue antigens in the thymus. It is a component of a multiprotein

Thymus

Periphery

FIGURE 14-2 Central T cell tolerance.

Recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection, or deletion) or the development of regulatory T cells that enter peripheral tissues.

Negative selection: deletion

Development of regulatory T cells

complex that is involved in transcriptional elongation and chromatin unwinding and remodeling. AIRE also contributes to pre-mRNA processing and induces the accumulation of processed spliced mRNAs (as opposed to unspliced mRNAs) of genes encoding peripheral tissue antigens. There is also evidence for AIRE-independent mechanisms of deletion in the thymus.

Many immature thymocytes with high-affinity receptors for self antigens that encounter these antigens in the thymus die by apoptosis. Negative selection occurs in double-positive T cells in the thymic cortex or newly generated single-positive cells in the medulla. In these locations, immature thymocytes with high-affinity receptors for self antigens encounter these antigens and die by apoptosis. T cell receptor (TCR) signaling in immature T cells leads to the activation of a protein called Bim, which triggers the mitochondrial pathway of apop-tosis. The mechanisms of apoptosis are described later in the chapter, when we discuss deletion as a mechanism of peripheral T cell tolerance. Clearly, immature and mature lymphocytes interpret antigen receptor signals differently—the former die and the latter are activated. The biochemical basis of this difference is not known.

Some self-reactive CD4+ T cells that see self antigens in the thymus are not deleted but instead differentiate into regulatory T cells specific for these antigens (see Fig. 14-2). The regulatory cells leave the thymus and inhibit responses against self tissues in the periphery. Interestingly, deficiency of the AIRE protein, which interferes with deletion of T cells reactive with some antigens in the thymus, does not appear to prevent the development of thymic regulatory T cells specific for the same self antigens. This observation suggests that the requirements for T cell deletion and regulatory T cell development in the thymus are different, but what determines the choice between cell death and development of regulatory T cells is not known. The characteristics and functions of regulatory T cells are described later in the context of peripheral tolerance because these cells suppress immune responses in the periphery.

Although the importance of central T cell tolerance has been clearly established in animal models, and the autoimmune polyendocrine syndrome suggests that it has a fundamental role for tolerance to some peripheral tissue antigens, it is still not known if a failure of central tolerance contributes to common human autoimmune diseases.

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