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Essay 3: T Cell Autoreactivity by Design: A Theoretical Framework for Understanding Tolerance, Autoimmunity and Transplant Rejection

Peter S. Heeger

During development in the thymus, T lymphocytes initially undergo positive selection so as to be able to preferentially recognize peptides expressed in the context of self-MHC molecules.1-4 Subsequently, the process of intrathymic negative selection results in deletion of T cell clones with "high affinity" for many self-antigens. The end result is that the mature T cell repertoire is capable of responding to an enormous variety of foreign antigens that it has not previously encountered.1-4 Nonetheless, central deletion of self-reactive T cells is incomplete and many relatively low affinity autoreactive T cells "escape" into the periphery.5 Standard paradigms in immunology view these escapees as an unwanted consequence of T cell development and as problematic to the host. In this view, the immune system must make use of a variety of peripheral tolerance mechanisms, including deletion, ignorance, anergy, suppression and end organ resistance, to control these potentially pathogenic T cells. Autoimmune disease results under rare circumstances when such tolerance mechanisms are overcome. While this paradigm can explain many experimental observations, it falls short of providing a comprehensive basis for our understanding of natural tolerance to self-antigens, and of experimentally induced tolerance, particularly in light of some recent observations regarding the development of autoreactive T cells following allograft transplantation. It is the goal of this commentary to provide an alternative framework within which one can incorporate the known experimental findings and potentially better account for them. It is hoped that the model will provoke thought and discussion.

Emerging results from multiple laboratories showing that autoreactive T cells can exhibit regulatory properties (reviewed in ref. 6) raise the possibility that one function of the T cell repertoire selection process is to seed the periphery with autoreactive T cells. Based on this postulate, one can then hypothesize that autoreactive T cells are present by design and play an active role in the maintenance of self-tolerance through dominant, interactive regulatory mechanisms (Table E3.1 and Fig. E3.1A). This concept stands in contradistinction to the standard view that autoreactive T cells represent an unwanted "side effect" of T cell

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