Th1 Rather Than Th0 Cytokines for Generation of CD4 Effectors Secreting High Antigen Density and IL-2 Are Required

C D4 ϩ T cells secreting restricted Th1 and Th2 patterns of cytokines differentially regulate infectious diseases and autoimmunity (1). Production of the Th1-specific cyto-kines, IFN-␥ and TNF␤, is required for clearance or control of many viral and protozoan infections, but the inflammatory reactions caused by these cytokines may mediate tissue destruction in autoimmune diseases such as rheumatoid arthritis (2) and multiple sclerosis (3). In contrast, the Th2-associated cytokines, IL-4 and IL-5, may be required for protection against helminth infections such as Nippostrongulus and Trichuris (4, 5), but may exacerbate or mediate allergic reactions. The roles of Th1 and Th2 responses in disease susceptibility have been studied extensively in parasite and in leishmanial models (6, 7). In the leishmanial model, resistant mice developed a Th1 response (mediated by IFN-␥), whereas susceptible mice developed an IL-4 dominated or Th2 response (6, 8). Importantly, susceptibility was reversed if IL-4 was blocked during the initial response (9). The generation of polarized Th1 and Th2 subsets is critical in determining the balance of cell-mediated and humoral immunoresponses and may determine the outcome of autoimmune reactions and infections by pathogens. Understanding the factors that promote preferential polarization of naive T cells and differentiation into effectors that have the capacity to be highly polarized (10) is important for understanding how the appropriate class(es) of immune response can be elicited. It is particularly clear that cytokines IL-4 and IFN-␥/IL-12 play critical roles in achieving Th2 and Th1 polarization, respectively, but their in situ source and which signals differentially regulate their production are less clear. One clear-cut murine model indicated that the bacterium Listeria monocytogenes, can interact with host cells such as macrophages, resulting in production of high levels of IL-12, which in turn drive a Th1-polarized response (11, 12). There have been a number of reports suggesting that the dose of Ag can determine the polarization of a CD4 response either in vivo (8, 13, 14) or in vitro (15–19). Low doses of Ag in vivo were reported to favor development of delayed-type hypersensitivity, presumably driven by Th1 polarization, while high doses favored Ab driven by Th2 polarization (8, 13). However, the strain of rat (13) or mouse (12, 19, 20) also had a major impact on polarization and could reverse the Ag dosage effect. It has been suggested that the naive T cell can respond differentially to different extents of receptor ligation (15, 21), a concept …