Tregs in T cell vaccination: exploring the regulation of regulation

T cell vaccination (TCV) activates Tregs of 2 kinds: anti-idiotypic (anti-id) and anti-ergotypic (anti-erg).These regulators furnish a useful view of the physiology of T cell regulation of the immune response.Anti-id Tregs recognize specific effector clones by their unique TCR CDR3 peptides; anti-id networks of CD4 + and CD8 + Tregs have been described in detail.Here we shall focus on anti-erg T regulators.Anti-erg T cells, unlike anti-id T cells, do not recognize the clonal identity of effector T cells; rather, anti-erg T cells recognize the state of activation of target effector T cells, irrespective of their TCR specificity.We consider several features of anti-erg T cells: their ontogeny, subset markers, and target ergotope molecules; mechanisms by which they regulate other T cells; mechanisms by which they get regulated; and therapeutic prospects for anti-erg upregulation and downregulation. HistoryT cell vaccination (TCV) became possible once we discovered how to raise and maintain in vitro autoimmune T cell lines and clones capable of adoptively transferring experimental autoimmune encephalomyelitis (EAE) to naive recipients (1).If EAE could be reduced to the actions of defined anti-myelin T cells, might EAE be resisted or aborted by vaccinating test rats with these same anti-myelin T cells suitably attenuated?The answer turned out to be yes; irradiated T cells specific for myelin basic protein (MBP) could indeed, when used as a vaccine, protect against future EAE induced by active autoimmunization to MBP (2).Surprisingly, vaccination with as few as one thousand T cells of a single clone could lead to the downregulation of as complex a disease as adjuvant arthritis (3).We concluded that the immune system could respond with great sensitivity to vaccination with its own agents and that the mechanism of immune regulation induced by TCV with a single clone could actively modify an entire polyclonal response (3).TCV was applied to various autoimmune disease models, including spontaneous diseases such as murine lupus (4) and type 1 diabetes mellitus (5), and the procedure is now being applied to human disease, mostly multiple sclerosis, by the groups of Zhang (6), Raus (7), Weiner (8), and others (9).But the remarkable sensitivity and effectiveness of TCV supported the idea that TCV might afford a view of natural immune regulation (10). Antigen-specific anti-id networksThe first regulators noted to be induced by TCV were anti-idiotypic (anti-id) T cells; both CD4 + and CD8 + anti-id T cells were detected in mice following TCV against EAE (11).TCR peptides were shown to be targets for regulation (5), demonstrating unequivocally that TCV could induce anti-id immunity.Recent work by Jiang, Chess, and colleagues (12), Kumar, Sercarz, and colleagues (13), and Cantor and colleagues (14, 15) is revealing the complexity of the antiid network of Tregs.A chain reaction begins with CD4 + anti-id T