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

Abstract

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.

Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

“…Pertinently, this infiltration consists of large focal infiltrates of T cells and DC/Mf, localized in the connective tissue of septa and capsule of the pancreas. Later, from birth to around weaning, they might be involved in peripheral tolerance as already described for skin epithelium (53). In NOD mice, the potential anomalies at lymphocyte levels include deficient central tolerance (54), which favors autoimmunity, and resistance to apoptosis (55,56), which can lead to the in situ accumulation of autoreactive and naive lymphocytes.…”

Murine CD8+ Recent Thymic Emigrants are αE Integrin-Positive and CC Chemokine Ligand 25 Responsive

“…Accordingly, ␣ E integrin expression on memory/effector CD8 ϩ T cells is restricted to certain mucosal or cutaneous populations, whereas CCR9 is found predominantly on small intestinal T cells (29). It has long been hypothesized that T cells can be tolerized to peripheral self-Ags upon leaving the thymus during the neonatal period, perhaps by trafficking through peripheral tissues in which they encounter Ag in the absence of necessary costimulatory signals (30,31). Thus, ␣ E integrin and CCR9 may direct early trafficking of RTE to peripheral sites, and this may constitute a final educational step in T cell maturation outside the thymus.…”

Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity

“…central tolerance ͉ self-antigen ͉ inflammation T olerance to self depends on potentially autoreactive lymphocytes encountering their autoantigen during differentiation in the thymus or after release into the periphery (1)(2)(3)(4). T lymphocytes specific for ubiquitous or bloodborne self-antigens are purged in the thymus (5).…”