Inhibition of T cell responses to autoantigens and allergens by CD25+ regulatory T cells from thymus, cord and adult blood

Abstract

Autoimmune diseases and allergies are a growing problem in the western world today. Tolerance is primarily established by clonal deletion in the thymus. Despite this auto-reactive T cells are normally present in most individuals, which suggests that mechanisms of peripheral tolerance operate to silence potentially pathogenic T cells. Current evidence points to CD4+CD25+ regulatory T cells (CD25+ Treg) as an active mechanism to suppress auto-reactive T cells that escape central tolerance. The aim of this thesis was to investigate if CD25+ Treg, similar to the murine counterpart, could be found and characterized in human lymphoid tissues. To this end, mononuclear cells were isolated from adult peripheral blood, cord blood and thymus and studied by flow cytometry and in functional studies of proliferation and cytokine production. We demonstrate that CD4+CD25+ T cells expressing intracellular CD152 (CTLA-4) and elevated levels of CD122, both hallmarks of murine CD25+Treg, are present in thymus as well as in cord and adult blood. We further show that CD25+ Treg in adults potently suppress T cell proliferation and IFN-gamma production in response to the auto-antigen myelin oligodendrocyte glycoprotein (MOG). By increasing the sensitivity in the suppression assay we found that also cord blood CD25+ Treg suppress MOG-induced proliferation and cytokine production. Interestingly, thymic CD25+ Treg did not inhibit the proliferation but did suppress IFN-gamma, which demonstrates the presence of MOG-specific CD25+ Treg in the thymus. In addition to the above-mentioned studies on healthy subjects, we investigated if patients suffering from birch allergy showed signs of defective CD25+ Treg when compared to healthy individuals. We found that birch allergic patients were unable to suppress Th2 cytokines during birch pollen season, while no differences were detected outside season when compared to healthy controls. In summary, our results demonstrate that CD25+ Treg are educated in the thymus but expand and improve their suppressive ability in the periphery mainly after birth.