Journal of Clinical Immunology, Vol. 19, No. 4 (July 1999) Special Articles Treatment of an Autoimmune Disease with "Classical" T Cell Veto: A Proposal UWE D. STAERZ1,2,3 and VAN QI1 Accepted: April 5, 1999 Immune responses protect against infectious diseases and cancers. In normal circumstances, the immune system is tolerant to self. However, under certain conditions this toler- ance is broken. The immune system attacks otherwise normal tissue. An autoimmune disease ensues. Strategies are now being sought that remove the pathogenic T cells without affecting other immune functions. "Classical" veto has been described as an immune suppressive mechanism able to remove T cells in a highly specific and effective manner. The present article briefly reviews the current knowledge on the develop- ment of autoreactive T cells and their regulation in the periphery. It describes "classical" veto, its mechanisms, and its novel applications. Finally, it argues that "classical" veto can be adapted to treat an autoimmune disease, such as type I diabetes mellitus. KEY WORDS: T cell veto; hybrid antibody; tolerance; autoimmune disease; diabetes mellitus. INTRODUCTION "Classical" veto has been described as an immune suppressive mechanism able to remove T cells in a highly specific and effective manner (1-3). Although it is questionable whether "classical" veto plays a crucial role in maintaining peripheral tolerance, it, nevertheless, might represent a useful mechanism for removing auto- reactive T cells from the peripheral repertoire (2). Here, 1 Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80207. 2 The Cancer Center and Department of Immunology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80220. 3 To whom correspondence should be addressed. 195 0271-9142/99/0700-0195$16.00/0 © 1999 Plenum Publishing Corporation we give an introduction to the veto phenomenon, its underlying mechanisms, and its potential applications. We argue that "classical" veto can be developed as a novel strategy to suppress immune responses and that it can be adapted to treat autoimmune diseases. Our dis- cussion is based on two premises: (i) suppression of T cells is crucial for the treatment of an autoimmune disease, and (ii) the goal of autoimmune disease thera- pies is the induction of specific immune tolerance. We explain the proposed veto approach using type I diabetes mellitus as the prototypical autoimmune disease. T CELL DEVELOPMENT AB T cells develop in the thymus from bone marrow-derived precursors. There, they rearrange T cell antigen receptor (TCR) variable genes, resulting in the surface expression of clonally distributed TCRs (4, 5). In the thymus, T cells are screened for func- tionality in a given MHC environment (positive selec- tion) (6-10) and for their autoaggressive potential (negative selection) (10, 11). During positive selec- tion, only those T cells that carry a TCR able to recognize antigen presented on self MHC molecules are allowed to mature and to emigrate into the periph- ery (6-9). T cells that fail this test are deleted. Although recognition events during positive selection are not fully understood, it is believed that they occur at a lowered affinity between the TCR and the thymic MHC/peptide complexes (12-22). Positive selection induces maturation of T cells resulting in changes of their surface and functional phenotype. As positive selection enriches for T cells able to recognize self-