Mechanisms of central and peripheral immune tolerance

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] The decision of a stem cell to develop into the myeloid or lymphoid lineage has been postulated to occur in the bone marrow. However, a marker of myeloidspecific progenitors in the thymus remains undefined. Herein, we show that IL-13R[alpha]1+ ETPs yield myeloid cells with no potential for maturation into T cells. These IL-13R[alpha]1+ progenitors are able to traffic from the bone marrow to the thymus and reconstituted thymic IL-13R[alpha]1+ ETPs in IL-13R[alpha]1-/- mice. Finally, the myeloid cells derived from IL-13R[alpha]1+ ETPs were able to contribute to T cell development. Thus, IL-13R[alpha]1 defines a new class of myeloid restricted ETPs that may play a role in central T cell tolerance and control of autoimmunity. When both central and peripheral tolerance mechanisms fail, autoimmune diseases such as multiple sclerosis can arise. In this study we have devised a method to induce tolerance through oral administration of an Ig chimera. Disease suppression was characterized by the systemic reduction of pro-inflammatory cytokines. Interestingly, upon oral treatment, LP APCs acquired a "tolerogenic" phenotype and were able to transfer tolerance to na[i with umlaut] ve mice induced for disease. Furthermore, transfer of tolerance by LP APCs was dependent upon an initial antigen-specific APC-T cell education in the gut. This study provides a novel mechanism of oral tolerance mediated by LP APCs, which can be utilized to induce tolerance to auto-antigens and reverse autoimmunity.