T cell vaccination induces T cell receptor V b-specific Qa-1-restricted regulatory CD 8 1 T cells

Vaccination of mice with activated autoantigen-reactive CD41 T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD81 regulatory T cells that are specific for pathogenic CD41 T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD81 T cells emerge that preferentially lyse and regulate activated autologous CD41 T cells in a T cell receptor (TCR) Vb-specific manner. This TCR Vb-specific regulation is not observed in b2-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vb8-specific Qa-1-restricted CD81 T cells are also induced by TCV with activated CD41 Vb81 T cells. These CD81 T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vb8. Further, CD81 T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD41Vb81 T cell clone specifically recognize other CD41 T cells and T cell tumors that express Vb8 and the syngeneic Qa-1a but not the allogeneic Qa-1b molecule. Thus, Vb-specific Qa-1-restricted CD81 T cells are induced by activated CD41 T cells. We suggest that these CD81 T cells may function to specifically regulate activated CD41 T cells during immune responses. The injection of naive animals with irradiated, antigenactivated, autoimmune CD41 T cells (T cell vaccination, TCV) was initially shown to protect rats from the subsequent induction of experimental allergic encephalomyelitis (EAE) (1). TCV has since been used with various degrees of success in a variety of animal models of autoimmunity (2) and in human autoimmune disease (3, 4). Although it has generally been thought that TCV augments the normal mechanisms employed by regulatory T cells to control the pathogenic potential andyor outgrowth of disease-causing T cells (5), the precise mechanisms by which TCV may ameliorate autoimmune manifestations are unknown. Several lines of evidence have suggested that CD81 T cells mediate the protective effect of TCV by down-regulating autoimmune T cells. For example, in studies of patients with multiple sclerosis, vaccination with autologous myelin basic protein (MBP)-reactive CD41 T cells (3) was shown to induce CD81 T cells that inhibited the antigen-induced proliferation of vaccine T cell clones and also specifically lysed the vaccine CD41 T cell clones in vitro. Similarly, the induction of EAE in rats by the injection of an encephalitogenic CD41 T cell clone was shown to induce CD81 T cells that recognize the encephalitogenic T cell clone in vitro and that, upon adoptive transfer, protect naive animals from the induction of EAE in vivo (6). These regulatory CD81 T cells preferentially recognized the vaccine T cells but not other T cells activated by different antigens. This clonotypic recognition by the CD81 cells suggested that the T cell receptor (TCR) or peptides derived from the TCR of autoimmune T cells are part of the target structure recognized by regulatory CD81 T cells. In this regard, TCR peptide immunization, although it may function by different mechanisms than TCV, efficiently prevents EAE in rats and mice (7–9) and thus provides additional evidence that the recognition of TCR structures is involved in the immunoregulation of EAE. However, regulatory CD81 T cells may not necessarily be specific for unique idiotypes expressed by particular autoimmune CD41 clones, and it is possible that CD81 regulatory cells may recognize variable portions of the TCR common to a set of TCRs. In this regard pathogenic autoimmune T cell populations, although not clonally homogeneous, are known to be restricted in terms of their recognition of particular peptide(s) and in their TCR gene usage (10–12). It is important to emphasize that although the above studies strongly suggest the possibility that TCV induces regulatory CD81 T cells that recognize the TCR or TCR peptide expressed by autologous CD41 T cells, there have been no experiments to directly demonstrate this point at a molecular level. In this regard, it is of interest that, in a different in vivo system, we have shown that the staphylococcal enterotoxin B (SEB)-induced deletion of CD41 Vb81 T cells depends, in part, on CD81 T cells. Moreover we have shown that, during the period of in vivo deletion of the CD41 Vb81 cells, one can culture from the animals CD81 cytotoxic T lymphocytes (CTL) that kill in vitro activated autologous CD41 Vb81 T cells but not T cells that express other Vb TCR. This TCR Vb-specific killing requires b2-microglobulin (b2m)-associated class I major histocompatibility complex (MHC) molecules expressed on the target cells and is inhibited by antisera to the class I-b MHC molecule Qa-1 but not by antibodies to conventional class I-a MHC molecules (13). Because the protective effect of TCV has been ascribed to the CD81 T cell recognition of TCR structures expressed by CD41 cells and because we had identified, in a different context, CD81 T cells that in fact recognize TCR structures on CD41 cells, we considered the possibility that TCV induces The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact. © 1998 by The National Academy of Sciences 0027-8424y98y954533-5$2.00y0 PNAS is available online at http:yywww.pnas. org. This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: TCV, T cell vaccination; EAE, experimental allergic encephalomyelitis; TCR, T cell receptor; MBP, myelin basic protein; SEB, staphyloccal enterotoxin B; CTL, cytotoxic T lymphocytes; b2m, b2-microglobulin; MHC, major histocompatibility complex; RT-PCR, reverse transcription–PCR; FACS, fluorescence-activated cell sorting; X-Gal, 5-bromo-4-chloro-3-indolyl b-D-galactoside. ¶To whom reprint requests should be addressed at: Dept. of Medicine, Division of Rheumatology, 630 W. 168th Street, College of Physicians and Surgeons, Columbia University, New York, NY 10032. e-mail: lc19@columbia.edu.