Joost P.M. van Meerwijk

Deficient T Cell Fate Specification in Mice with an Induced Inactivation of Notch1

Notch proteins are cell surface receptors that mediate developmental cell specification events. To explore the function of murine Notch1, an essential portion of the gene was flanked with loxP sites and inactivation induced via interferon-regulated Cre recombinase. Mice with a neonatally induced loss of Notch1 function were transiently growth retarded and had a severe deficiency in thymocyte development. Competitive repopulation of lethally irradiated wild-type hosts with wild-type- and Notch1-deficient bone marrow revealed a cell autonomous blockage in T cell development at an early stage, before expression of T cell lineage markers. Notch1-deficient bone marrow did, however, contribute normally to all other hematopoietic lineages. These findings suggest that Notch1 plays an obligatory and selective role in T cell lineage induction.

Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors

Most T lymphocytes, including regulatory T cells (Treg cells), differentiate in the thymus. The age-dependent involution of this organ leads to decreasing production of T cells. Here we found that the output of new Treg cells from the thymus decreased substantially more than that of conventional T cells. Peripheral mouse and human Treg cells recirculated back to the thymus, where they constituted a large proportion of the pool of Treg cells and displayed an activated and differentiated phenotype. In the thymus, the recirculating cells exerted their regulatory function by inhibiting interleukin 2 (IL-2)-dependent de novo differentiation of Treg cells. Thus, Treg cell development is controlled by a negative feedback loop in which mature progeny cells return to the thymus and restrain development of precursors of Treg cells.

Thymic selection and lineage commitment of CD4(+)Foxp3(+) regulatory T lymphocytes.

Regulatory T lymphocytes play a central role in the control of a variety of immune-responses. Their absence in humans and in experimental animal models leads to severe autoimmune and inflammatory disorders. Consistent with their major role in prevention of autoimmune pathology, their repertoire is enriched in autospecific cells. Probably the majority of regulatory T cells develop in the thymus. How T cell-precursors choose between the conventional versus regulatory T cell lineages remains an unanswered question. More is known about selection of regulatory T cell precursors. Positive selection of these cells is favored by high affinity interactions with MHC class II/peptide ligands expressed by thymic epithelial or dendritic cells. They are also known to be relatively resistant to negative selection. These two parameters allow for the generation of the autoreactive regulatory T cell repertoire, and clearly distinguish selection-criteria of conventional versus regulatory T cell-precursors. It will now be important to elucidate the molecular mechanisms involved in the intrathymic choice of the regulatory T cell-lineage.

Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review

The generation and function of immuno-suppressive regulatory T lymphocytes (Treg), which can differentiate in the thymus (tTreg) or in the periphery (pTreg), are regulated in an age-dependent manner. tTreg are produced at high levels in the first weeks of age, when they expand and colonize secondary lymphoid organs and peripheral tissues to protect the organism from autoimmune diseases and to promote tissue repair. Once this population of Treg is operational in the periphery, at puberty, thymic output of Treg declines, but self-reactive tTreg generated early on in life are maintained over time and play a major role in preserving homeostasis of the immune system. Extra-thymic pTreg differentiation declines later on in life. pTreg generated throughout life mainly protect the organism from chronic inflammation and the semi-allogeneic fetus from rejection. In this review, age-dependent modulation of the production and function of these two populations of Treg is described.

Antigen-presenting cells and T-lymphocytes homing to the thymus shape T cell development

Hematopoietic precursors entering the thymus undergo a maturation process leading to the generation of a variety of T cell subsets that migrate to the periphery to perform their effector functions. This maturation process is strictly regulated by multiple interactions of developing T cells with thymic stroma cells. Signals received via the T cell receptor for antigen, co-stimulatory molecules and cytokines will determine, through thymic selection and lineage choice, thymocyte-fate. Recently, different populations of peripheral antigen presenting cells and T cells have been reported to enter the thymus. Here we review how these cells migrating from the periphery to the thymus modulate T cell development.