Clinical Immunology and Immunopathology

cytokines, and then the phenomenon is resurrected unThis paper presents some questions and issues reder a different name. garding the concept of the Th1/Th2 dichotomy and Parenthetically, the phenomenon of the ‘‘T suppressummarizes results using an hsp60 peptide to treat the sor cell’’ has been unusually resistant to its molecular spontaneous autoimmune process of diabetes in NOD resurrection. Reputable immunologists may continue mice. q 1997 Academic Press to deny the existence of antigen-specific T suppressor cells, despite their acceptance of the fact that a T cell can secrete a ‘‘suppressor’’ cytokine (TGFb, IL-4, ILINTRODUCTION 10) in response to a specific antigen. There may be a good reason for this persisting dislike of a term that The Th1/Th2 dichotomy (1) is shorthand for the obseems to have a molecular basis: cytokines are pleiotroservation that the antigen-specific activation of CD4 pic and a particular cytokine such as TGFb may be T cells can lead to two seemingly opposed biological suppressive for one target (Th1 T cells, for example) outcomes: the secretion of ‘‘proinflammatory’’ cytokines and, at the same time, stimulatory for a different target (the Th1 phenotype) or the secretion of ‘‘anti-inflam(fibroblasts, for example). Th1/Th2 terminology refers matory’’ cytokines (the Th2 phenotype). The Th1/Th2 directly to packages of cytokines and only indirectly to dichotomy is only two of several response phenotypes cellular behavior. Th2 and Th1 T cells may, without that can be elicited by a single antigen. For example, offending a single immunologist, suppress the activithe CD8 T-cell response can be expressed as cytotoxicties of the other T-cell type while enhancing the activiity or suppression, and a single antibody specificity, ties of their own camp. Nevertheless, the Th1/Th2 diexpressed by the antibody’s variable moiety, can mobichotomy carries the hazard of its own phenomenologilize a variety of biological effects, depending on the cal oversimplification, an issue to which I shall return class and isotype of the constant region of the antibody. at the end. Thus, when mounting a response, the immune system has to weigh options. The Th1/Th2 cytokine option is TYPE I DIABETES currently popular because this dichotomy can influence, for better or worse, the fate of the individual responding to an infectious agent, to tumor cells, or to a Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), designates the diabetes that results from self-antigen in an autoimmune situation. Historically, the phenomenon we now call Th1/Th2 was described autoimmune destruction of the insulin-producing b cells of the pancreatic islets (4). The disease used to be long ago as ‘‘immune deviation,’’ denoting the capacity of an immune response to be expressed primarily either called juvenile diabetes because it appeared to be limited to young persons, in contrast to adult-onset nonby antibody production or by ‘‘cell-mediated’’ immunity (2). Early evidence suggested that different populations insulin-dependent diabetes mellitus. However, it is now clear that the incidence of type I diabetes is inof T cells provided help for antibody production and mediated cellular reactions (3). The renaissance of increasing and the disease can develop in adults into the fifth and sixth decades of life. Although the developterest in T-cell classes springs from the discovery of cytokines and their classification into Th1 and Th2 ment of IDDM requires a susceptible genetic background with a strong HLA effect (5), the autoimmune groupings (1). Such is the nature of the scientific enterprise; a phenomenon, such as immune deviation, will process would seem to require environmental triggering. The increasing incidence of IDDM in Northern lose the attention of the research community unless study of the phenomenon leads to a molecular mechaindustrialized societies is compatible with environmental toxins as triggers. nism that explains it. The decline of interest in immune deviation could only be reversed by the discovery of It has been difficult to study the natural history of