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EVOLUTION OF THE TYPE-1 (Th1)–TYPE-2 (Th2) CYTOKINE PARADIGM

1999; Elsevier BV; Volume: 13; Issue: 1 Linguagem: Inglês

10.1016/s0891-5520(05)70039-8

1557-9824

Daniel R. Lucey,

T-cell and B-cell Immunology

The field of type-1–type-2 cytokine immunology has evolved rapidly since its inception in 1986 and has begun to be applied to the field of vaccinology since the early 1990s. This article focuses on the evolution of the type-1–type-2 cytokine model and provides an overview of how this model is being applied to vaccine development. The seminal discovery that cloned murine T-helper (Th) lymphocytes could be divided into two subsets (Th1 and Th2), based on their cytokine production, was first reported in 1986. Th1 clones were characterized by the production of interferon (IFN)-γ, whereas Th2 clones produced interleukin (IL)-4.16, 19 Th1 clones also produced IL-2, whereas TH2 clones were later found to produce IL-5, IL-6, and IL-10. Some Th1-Th2 cytokines were cross-regulatory: IFN-γ inhibited production of IL-4 from Th2 clones, whereas IL-4 inhibited production of IFN-γ from Th1 clones (Table 1).17, 18 Th0 clones were described as those that could produce cytokines of both Th1 and Th2 clones. Thp clones served as precursors to the other Th clones. Th1 clones were found to provide helper activity for cell-mediated immunity (CMI), including activated macrophages, cytotoxic T cells, and delayed-type hypersensitivity reactions. Conversely, Th2 clones favored B-cell development and antibody production. This apparent dichotomy between CMI and antibody provided insight into the century-old controversy concerning the relative importance of cellular versus humoral immunity against infectious diseases. Silverstein29 has traced this controversy to the late nineteenth century when Metchnikoff took the view that the critical protective immune response was cellular (phagocytic) immunity, and von Behring, Ehrlich, and colleagues championed the opposing view that humoral immunity was most critical. During that time, Wright and Douglas attempted, with limited success, to reconcile the cellular and humoral schools and to emphasize the interdependence of these two arms of the immune system. The discovery of Th1 and Th2 lymphocytes a century later provided new insight into both the interdependence and the cross-regulatory nature of cellular and humoral immunology. These Th1-Th2 cells and their respective cytokines can be conceptualized as the central mechanism determining the relative strengths of the immune response to microbial antigens along the cellular and humoral pathways. Complexities to this straightforward Th1/Th2 dichotomy, however, soon became apparent. For example, Th1 clones increase production of certain antibody isotypes (e.g., IgG2a in mice) and therefore do not solely mediate CMI. Some cytokines (e.g., IL-12) associated with the generation of cellular (Th1) immunity are not made by T cells at all, whereas many Th1 and Th2 cytokines are made by cells other than CD4+ T-helper cells (Table 2). Many human T cells (Th0) cannot be categorized as simply Th1 or Th2 because they produce cytokines characteristic of both subsets. Some T cells produce one, but not all, of the defining Th1-Th2 cytokines. Some cytokines are neither Th1 or Th2, but can modulate cellular or humoral immune responses, whereas some infectious diseases appear to require both cellular (Th1) and humoral (Th2) responses for their control. Nevertheless, application of the murine Th1-Th2 model to the pathogenesis, treatment, and prevention of certain infectious diseases provided critical new insights. As one clear-cut example, Leishmania major infection in specific murine models was found to be associated with disease in a Th2 (IL-4), antibody-dominant context, but with lack of disease or cure in a Th1 (IFN-γ or IL-12) CMI-dominant context.16, 17, 18, 19 Therefore, the search began for analogous findings in humans despite the complexities in the Th1-Th2 paradigm, such as those listed previously.12, 20 In the early 1990s, evidence for human Th1 and Th2 lymphocytes was first reported,10, 21, 23, 33, 36 either in cloned T cells; in peripheral blood; or in tissue-specific compartments (e.g., synovial fluid). At the same time, the nomenclature of type-1– type-2 cytokines began to evolve in place of the terms Th1/Th2, emphasizing the immunologic effect of the respective cytokines rather than their cell of origin. The type-1 and type-2 cytokine nomenclature was originally suggested by Bloom and colleagues5 in reference to CD8+ cells as a source of Th1 and Th2 cytokines. We have recently reviewed the literature on type-1 and type-2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases.12 Initial reports have suggested a relative predominance of type-1 or type-2 cytokine responses in more than 20 human infectious diseases, including parasitic, fungal, viral, and bacterial diseases. For example, chronic Lyme arthritis is characterized by a dominant type-1 cytokine process involving particularly the T cells in the involved synovium rather than peripheral blood T cells. On the other hand, chronic helminthic parasitic infections, and eosinophilic disorders in general, appear to be predominantly type-2 cytokine conditions. Some diseases, such as leprosy, have diverse clinical manifestations that may be closely paralleled by their type-1–type-2 cytokine profile. For example, tuberculoid leprosy is predominantly a type-1 cytokine condition, whereas lepromatous leprosy is predominantly a type-2 condition. The type-1–type-2 cytokine nomenclature has evolved to include non–T-cell leukocytes, such as monocyte-macrophages, dendritic cells, natural killer cells, B cells, mast cells, and eosinophils, all of which can produce cytokines originally attributed only to Th1 or Th2 cells (see Table 2). For example, IL-12 is not produced by any T cells, but by several types of antigen-presenting cells (especially macrophages and dendritic cells). IL-12 induces IFN-γ and is critical to the development of a type-1 cytokine environment. Nonleukocyte cellular sources of type-1–type-2 cytokines also are recognized.