Cytokines and the regulation of tolerance.

ture regarding the regulation of the immune responses and the induction of tolerance, a process critical to the understanding of the rejection of solid organ grafts, graft versus host disease, and autoimmune disorders. Tolerance comes in two forms: In central tolerance , T cells that respond to a specific antigen are deleted in the thymus before emigrating to the " periphery " or systemic circulation. Peripheral tolerance , on the other hand, refers to the regulation or suppression of mature lymphocytes that are already in circulation. In the past several years, much attention has focused on the role of T cells of different subtypes and the significance of various cytokines in generating tolerance, especially the peripheral form (1). Although both CD4 + and CD8 + T cells secrete cytokines, CD4 + cells secrete them in significantly larger quantities (hence, the T " helper " [Th] nomenclature). CD4 + T cells can be further subdivided by the patterns of cytokine released: Th1 cells produce IL-2 and IFN-γ, which are critical to cell-mediated immunity, whereas Th2 cells produce IL-4, IL-5, and IL-10, which promote antibody production and humoral immunity (2). When naive T cells first exit the thymus, they can secrete both Th1 and Th2 cytokines and are termed Th0, but as these cells encounter antigen and become memory cells, their cytokine patterns become fixed as either Th1 or Th2. Responses by a given T-cell clone to a particular antigen tend to fall into one or the other pattern (3), especially in rodents, in which T-cell responses are more rigidly fixed than in humans. The exclusive expression of Th1 and Th2 responses arises in part because these T-cell subtypes suppress each other's function (4, 5). This cross-regulation has given rise to the " Th1/Th2 " paradigm, in which a dominance of proinflammatory Th1 cytokines causes destruction of target tissues and a loss of tolerance, whereas the dominance of Th2 cytokines suppresses the Th1 response and promotes tolerance (6–11). As with many paradigms, the simplicity of Th1/Th2 dichotomy is both its strength and its weakness. This model appears to describe many responses to foreign cells and proteins, but anomalies have been noted, and the study by Coudert and colleagues in this issue of the JCI (12) provides an example of a Th2 cytokine response that activates humoral immunity but does not engender tolerance. Indeed, these investigators show that an enhanced Th2 (and presumably …