Biomedical subjects

J Alferink

Publications and source records attributed to J Alferink.

8 recordsLinked to original sources

PubMed1999

Peripheral T-cell tolerance: the contribution of permissive T-cell migration into parenchymal tissues of the neonate.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent chronic autoimmune diseases. Since naive T lymphocytes do not circulate through extralymphoid tissues the concept has emerged that peripheral T cells ignore tissue-specific antigens unless they are presented by professional antigen-presenting cells in the lymphoid compartments. However, this view pays attention only to experiments performed in adult animals. This report reviews the evidence that tissues of neonatal mice, in contrast to adults, exhibit high accessibility for naive T cells, thereby allowing the direct contact with tissue-specific self-antigens on parenchymal cells during neonatal life and tolerance induction to such self-antigens. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a major histocompatibility class I antigen expressed on keratinocytes only during a neonatal period and not during adulthood. Blockade of T-cell migration neonatally prevented tolerance induction. The neonatally induced tolerance is maintained during adulthood, apparently by a dominant regulatory mechanism. Thus, parenchymal cells and T-cell migration in the neonate contribute to the control of autoreactive T cells.

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PubMed1998

Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking.

Self tolerance is acquired by the developing immune system. As reported here, particular properties of the neonatal tissue contribute to this process. Neonatal skin, but not adult skin, was accessible for naïve CD8 T cells. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a skin-expressed major histocompatibility complex class I antigen only during a neonatal period but not during adulthood. Blockade of T cell migration neonatally prevented tolerance induction. Thus, T cell trafficking through nonlymphoid tissues in the neonate is crucial for the establishment of self tolerance to sessile, skin-expressed antigens.

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PubMed1998

Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment.

Peripheral tolerance is considered to be a safeguard against autoimmunity. Using a TCR-transgenic mouse system displaying peripheral tolerance against a liver-specific MHC class I Kb antigen, we investigated whether the breaking of tolerance would result in autoimmunity. Reversal of tolerance was achieved by simultaneous challenge with cells expressing the Kb autoantigen and IL-2. Tolerance could not be broken with IL-2 alone or when Kb- and IL-2-expressing cells were applied to different sites of the mice. However, despite the presence of activated autoreactive T cells that were able to reject Kb-positive grafts no autoaggression against the Kb-positive liver was observed. These results indicate that breaking of tolerance per se is not sufficient to cause liver-specific autoimmunity. However, when in addition to breaking tolerance the mice were infected with a liver-specific pathogen, autoaggression occurred. Thus, in this system at least two independent steps seem to be required for organ-specific autoimmunity: reversal of peripheral tolerance resulting in functional activation of autoreactive T cells and conditioning of the liver microenvironment which enables the activated T cells to cause tissue damage.

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PubMed1998

A two-step model for the induction of organ-specific autoimmunity.

Peripheral tolerance is considered to be a safeguard against autoimmunity but the mere existence of anergic T cells renders them potentially dangerous. Using transgenic mice that were tolerant to a foreign MHC class I antigen (Kb) exclusively expressed in the liver, we investigated whether reversal of tolerance in vivo would directly result in autoimmunity. Breaking of tolerance was achieved by application of tumour cells expressing both Kb and interleukin 2. Despite the fact that the respective mice were now able to reject Kb-positive grafts, the reversed T cells did not infiltrate and attack the Kb-positive liver. However, when the liver was 'conditioned' through an inflammatory reaction either by irradiation or by infection with Listeria, massive T cell infiltration and liver damage were observed in the reversed mice. The results show that at least two steps are required for autoimmunity: (1) activation of antigen-specific T cells, and (2) conditioning of the target organ. It will be important to determine the factors leading to conditioning but it is likely that adhesion molecules are involved. These experiments are not only of relevance for treatment of autoimmune disease but also for tumour therapy.

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PubMed1998

Tolerance induction in mature T lymphocytes.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent autoimmunity. Recently, we were able to demonstrate the existence of peripheral tolerance in double-transgenic mice expressing the foreign histocompatibility antigen H-2Kb exclusively outside the thymus and a T cell receptor (Des.TCR) directed against the Kb molecule. In mice expressing Kb only on keratinocytes anti-Kb T cells were still present but failed to reject Kb-positive tissue grafts. This observation would imply a continuous migration of naïve T cells exported from the thymus into non-lymphoid tissues where these fresh thymic emigrants would need to be tolerized. However, this is in contrast to the view that migration to peripheral tissues is restricted to activated T cells. To investigate whether there is a continuous process of tolerization of naïve T cells in adult DES.TCR x 2.4Ker-Kb mice, 2.4Ker-Kb mice were crossed with Rag-2-deficient mice and reconstituted with bone marrow cells of Des.TCR transgenic mice (Des.TCR x 2.4Ker-Kb.Rag-2-). Tolerance was not observed in these chimeric mice. We conclude from these results that in contrast to the neonate the adult physiological environment does not allow tolerance induction to antigens expressed on keratinocytes in T cells newly exported from the thymus. Furthermore, we have to postulate regulatory events responsible for the maintenance of peripheral tolerance in the adult Des.TCR x 2.4Ker-Kb animals.

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PubMed1995

T cell awareness of paternal alloantigens during pregnancy.

During pregnancy a semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens. A mouse transgenic for a T cell receptor recognizing the major histocompatibility (MHC) antigen H-2Kb was used to follow the fate of T cells reactive to paternal alloantigens. In contrast to syngeneic and third-party allogeneic pregnancies, mice bearing a Kb-positive conceptus had reduced numbers of Kb-reactive T cells and accepted Kb-positive tumor grafts. T cell phenotype and responsiveness were restored after delivery. Thus, during pregnancy maternal T cells acquire a transient state of tolerance specific for paternal alloantigens.

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PubMed1995

Long life span of tolerant T cells and the role of antigen in maintenance of peripheral tolerance.

To follow the fate of tolerant T cells in vivo we used a transgenic mouse model in which peripheral T cell tolerance was based on a non-deletional mechanism. These mice expressed two transgenes: the MHC class I molecule Kb under the keratin IV promoter on keratinocytes (2.4 KerIV-Kb) and an anti-Kb TCR identified by the anti-clonotypic antibody Désiré-1 (DES-TCR). Although these mice were tolerant to Kb skin grafts, CD8+DES+ T cells were present in their lymphoid organs in the same numbers as in Kb-reactive DES-TCR single-transgenic mice. The unresponsiveness towards Kb grafts suggested previous contact of the CD8+DES+ T cells with the Kb molecule on keratinocytes, but the evidence was indirect. The present study demonstrates enhanced levels of activation markers like CD44 and CD2 on the tolerant T cells, indicating contact with the Kb molecule. Continuous presence of antigen was required for maintenance of the tolerant state as shown by transfer of tolerant T cells into Kb-negative nu/nu BALB/c mice. Three days after cell transfer most recipients were still tolerant and accepted Kb-positive skin grafts, but 2 weeks after transfer the transferred cells had recovered their responsiveness and rejected Kb grafts. In order to see if contact with the tolerogen would eventually drive the tolerant cells into cell death, the life span of tolerant CD8+DES+ cells was measured in thymectomized DES-TCR x 2.4 KerIV-Kb double-transgenic mice. The tolerant cells were found to have a life span of at least 8 weeks, which was comparable with the life span of non-tolerant CD8+DES+ cells from DES-TCR single-transgenic mice. Thus, tolerant T cell populations can be long-lived and need continuous contact with the tolerogen to remain tolerant.

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PubMed1994

Tolerance induction as a multi-step process.

Tolerant T cells are characterized by their partial or full resistance to activation by antigen. We investigated whether tolerant T cells were still receptive to further tolerogenic signals. T cells expressing a transgenic T cell receptor (TCR) specific for the major histocompatibility complex (MHC) class I molecule Kb were deleted in mice carrying Kb but not in mice expressing the mutant Kb-molecule Kbm1 [TCR (H-2bm1 x k) mice]. These T cells were tolerant in vivo but could be activated in vitro by the Kb antigen. This in vitro reactivity was abolished after the tolerant T cells encountered Kb-positive cells that had been intravenously injected. Furthermore, in TCR (H-2bm1 x k) mice expressing Kb only on hepatocytes, no T lymphocytes bearing the transgenic TCR could be found in the periphery, indicating that the additional contact with Kb on hepatocytes led to deletion of the tolerant T cells. These findings demonstrate that tolerance induction can be a multi-step process.

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