Peripheral regulation of the class of T cell effector functions the phenomenon of education

T cells which were positively selected in the thymus following 'low' affinity interactions with TE cells, and passed the 'deleting HC filter', leave the thymus in a 'resting' immunocompetent state. They will constitute the vast majority of the peripheral T cell compartment, and are supposed to recirculate continuously through the body, 'chasing' possible invaders. Their lifespan in normal animals is of the order of 1-2 months and they will die after this period if they do not encounter antigen. This picture seems, however, not to be as monotonous as it looks for the notion has been that every naive T cell reaches the periphery still in a critical state of sensitivity to TCR ligation. At this stage they are called 'recent thymic emigrants' (RTEs) as opposed to T cells that have already been in the periphery for longer. These we shall call peripheral, mature and resident iPMRi lymphocytes.

The reason to postulate this 'critical period', which could last for few hours or few days (no one knows), is directly linked to the necessity of tolerizing self reactive T cells to tissue-specific antigens not present in the thymus, and thus rescue the Lederberg concept of sensitivity to deletion/anergy of immature T cells for peripheral T cells. We know now that this is wrong: RTEs as well as mature T cells from the thymus can reject allogeneic skin transplants with the same efficiency as PMR T lymphocytes.

Interestingly, however, experimental evidence was obtained on the distinct sensitivity of RTF. and PRM states to regulatory T cell-mediated suppression and 'education', thus supporting the existence of a post-thymic 'critical period' of lymphocyte functional commitment.

In TE-chimeras regulatory CD4 T cells are positively selected by the allogeneic TE, escape deletion because hematopoietic APCs express a distinct major histocompatibility complex (MHC), and can thus be produced throughout life. This contrasts with the

Avidity
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Figure 1 Thymic T cell selection is a function of the avidity of TCR-MHC-peptide interactions. For any given T cell the probabilities of positive selection, activation and deletion are described by logistic functions with thresholds A1, A2 and A3, respectively (dashed lines). For increasing levels of avidity, the products of these probabilities result in no selection, positive selection into resting state (naive T cell), positive selection and activation (regulatory T cell) (shaded area in the plot), and deletion, respectively. The figure compares the selective properties of TE (A) and HC (B). It should be noted that T cells selected with a given phenotype (naive or regulatory) on TE can be deleted by later interaction with thymic HC (as is the case for most regulatory cells in B, given the relative position of the deletion curves for the two types of stroma cells), but cannot be switched to another phenotype by a second interaction.

situation in normal mice, where the progressive colonization of the thymus by HCs is expected to restrict the putative generation of regulatory T cells to the perinatal period of thymic development. Transposing the observations on TE-chimeras to normal tissue-specific tolerance, other mechanisms have to be invoked. Thus, since the numbers of peripheral T cells increase by 1000-fold in the first 3-4 weeks of life by accumulation of RTEs, putative regulatory T cells produced around birth would be diluted out in the periphery by high numbers of tissue-specific T cells produced throughout life.

To answer these questions we have recently demonstrated that:

1. RTEs are more susceptible to suppression by TE-selected regulatory T cells than PRM T cells.

2. Both RTEs and PRM T cells display the ability to reject tissue grafts in the absence of TE-T cells.

3. The peripheral encounter of antigenic tissue per se does not tolerize RTEs, demonstrating both the immunocompetence of cells at this differen tiative stage, and immunogenic antigen-presentation by the grafted tissue.

4. RTEs are particularly sensitive to dominant tolerance mechanisms.

5. TE-selected, regulatory CD4 T cells are capable, together with specific antigen, of recruiting immunocompetent T lymphocytes into similar regulatory functions.

6. Only RTEs, not PRM T cells, seem susceptible to being 'educated' into regulatory functions.

7. Both CD4 and CD 8 RTEs can be recruited into regulatory functions, each population mediating peripheral mechanisms of tolerance.

All these types of lymphocyte interactions are schematically represented in Figure 2.

T cells whose receptor happens to recognize tissue-specific antigens (not expressed in the thymus) will leave the thymus in a resting state, uncommitted to any effector function.

The functional pathway of differentiation of naïve

Education

» i Regulatory Tcefl

Education

Figure 2 The three distinct fates of peripheral naive T cells recognizing specific antigen on an APC. Regulatory T cells recognize in peripheral tissues MHC-peptide complexes towards which they were selected and activated on TE (ubiquitous peptides). Naive T cells (RTEs or PMRs) respond to tissue peptides that are absent from the thymus (tissue specific). The specificities of the regulatory and naive T cells are thus unrelated. In (B), the variable ratio' applies to the numbers of regulatory versus PMR T cells interacting on the same APC.

Figure 2 The three distinct fates of peripheral naive T cells recognizing specific antigen on an APC. Regulatory T cells recognize in peripheral tissues MHC-peptide complexes towards which they were selected and activated on TE (ubiquitous peptides). Naive T cells (RTEs or PMRs) respond to tissue peptides that are absent from the thymus (tissue specific). The specificities of the regulatory and naive T cells are thus unrelated. In (B), the variable ratio' applies to the numbers of regulatory versus PMR T cells interacting on the same APC.

T cells recognizing specific antigen on a peripheral APC ('professional' or otherwise) will be dictated by the local environmental conditions. As shown in Figure 2 three distinct situations can be envisaged.

1. The naive T cell is a RTE, and the APC it interacts with is concommitantly recognized by regulatory T cells. Under these circumstances the naive cell will be 'educated' such that it itself becomes a regulatory T cell. This is the situation that is expected to occur during the ontogenic development for self reactive cells.

The naive T cell is a PMR T cell, and the APC it interacts with is concommitantly recognized by regulatory T cells. In this case the outcome depends on the ratio of regulatory/PMR T cells at the surface of the APC. Thus, for high ratios, the PMR T cell is suppressed and remains naive. For low ratios, the regulatory T cells are too rare to control the naive PMR cells, which are therefore activated and become aggressive. The first case is the situation that again should occur for tissue-specific T cells that did not have the opportunity to encounter self antigen at the stage of RTE. The second case would represent the local conditions to be set up for the development of an immune response against, for example, a viral antigen in the tissues. 3. The naive T cell is either a RTE or a PMR T cell, and the APC it interacts with is not simultaneously recognized by regulatory T cells. In this case, the T cell is activated and displays an aggressive functional phenotype.

Finally, Figure 3 shows how the process of peripheral T cell education during development shifts the repertoire of regulatory T cells from TE selected to tissue specific.

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