Lymphopenia and autoimmune diseases

More than 30 years ago, the occurrence of spontaneous autoimmune thyroiditis was observed in rodents that were made severely T-cell lymphopenic by neonatal thymectomy or by thymectomy at week five after birth together with concomitant low dose irradiation [1,2]. Following these reports, numerous studies have shown that manipulations that generate functional T-cell lymphopenia result in the development of a variety of organ-specific autoimmune diseases in animal models (reviewed in [3]). Impressive examples of such manipulations include: IL-2 knockout mice, that develop prominent autoimmune colitis [4]; T-cell receptor-alpha chain deficient mice, that develop inflammatory bowel disease associated with an array of autoantibodies [5,6]; T-cell receptor-α chain transgenic mice [7]; neonatal application of cytotoxic intervention protocols, such as cyclosporine A [8]; total lymphoid irradiation [9] or thymectomy [10]; and lymphotoxic treatment of adult animals [11]. It was subsequently found that adoptive transfer of T cells into congenic immunocompromised hosts initiated the spontaneous development of aggressive inflammatory autoimmunity in recipients [12]. Further studies revealed that the development of autoimmunity in hosts was critically dependent on both transfer of alpha/beta CD4-positive T cells and T-cell deficiency in the recipients. Together, these data indicate that lymphopenia promotes the induction of autoimmune inflammation by self-reactive syngeneic peripheral blood CD4 T cells. Indeed it could be demonstrated that when lymphopenia was induced in mice by cytotoxic treatment with cyclophosphamide or streptozotocin, the peripheral T-cell population that emerged consisted mainly of IFN-γ secreting proinflammatory Th1-like cells [13]. However, it was unclear whether the appearance of these cells reflected de novo priming of autoreactive inflammatory T cells in the lymphopenic host or the preferential outgrowth of pre-existing T cells of autoimmune specificity, facilitated by a breakdown of suppressive mechanisms. Thus, the critical question for the understanding of autoimmunity, namely how the causative autoimmune response was initiated, remained unresolved. Recent studies have shed light on the mechanisms that lead to the breakdown of peripheral tolerance in lympho-penic animals. Powrie and her group demonstrated that colitogenic inflammatory CD4 T cells exist in normal mice [14]. Importantly, their function is controlled in healthy animals by regulatory mechanisms involving IL-10 and a distinct subset of CD4 T cells characterized by the expression of CD25. Moreover, adoptive transfer of these CD25-positive CD4 T cells prevented T-cell-mediated immune pathology and even ameliorated established gastrointestinal inflammation in the CD4 CD45RB high T-cell transfer model of inflammatory bowel disease [15]. These findings emphasize that autoreactive T cells …