Multiple Pathways for the Initiation of T Helper 2 (Th2) Responses

S ince the initial descriptions of CD4 1 T cell subsets with distinct functions and cytokine production profiles, the question of how these cells originate during an immune response has been asked. Both Th1 and Th2 cells can develop from naive, peripheral CD4 1 T cell (Thp) populations, and individual Thp cells appear capable of differentiating into either Th subset (reviewed in reference 1). The differentiation process is initiated by ligation of the TCR, but additional signals are required for maturation into cells capable of producing high levels of cytokines upon restimulation. The most clearly defined differentiation inducers are themselves cytokines: IFNg and IL-12 for Th1, and IL-4 for Th2 induction. Thus, understanding the cellular origin and control of production of these cytokines during a primary immune response is central to understanding the genesis of Th1 and Th2 responses. The principal early events that lead to Th1 differentiation in mice infected with any of a number of intracellular pathogens are reasonably well understood. These begin with the production of IL-12 by macrophages responding either to microbial products or to direct infection and the subsequent induction, by IL-12, of IFNg production by NK cells (reviewed in reference 2). This response usually occurs within 24 h of infection and constitutes the most effective form of innate immunity for this class of pathogens. Naive T cells initiating a specific response to the pathogen in a microenvironment dominated by IFNg and IL-12 develop preferentially into Th1 cells. Thus, the effector functions of the innate response that are most appropriate for the control of these pathogens are conserved in the subsequent antigen-specific T cell response. The sources and modes of regulation of the initial IL-4 needed to induce Th2 development have, in contrast, not been so clearly defined. Candidate sources of IL-4 include atypical subsets of T cells not restricted by class II MHC (including NK1 1 CD4 1 T cells), conventional CD4 1 memory T cells, eosinophils, and cells of the mast cell/basophil lineage. In this issue, a paper by Rincón et al. (3) now suggests that naive T cells themselves can be the source of IL-4 that leads to their own Th2 development and that IL-6 is a potent inducer of this IL-4. The basic experimental system used in this work consisted of purified mouse CD4 1 T cells stimulated in vitro for 4 d. The cells were then harvested, washed, and restimulated, and the supernatants were assayed for IL-4 and IFNg as measures of Th2 or Th1 differentiation, respectively. Most experiments employed the polyclonal stimulators Concanavalin A or anti-CD3, but a few experiments were performed with T cells from a TCR-transgenic mouse stimulated with the appropriate peptide epitope. The addition of either IL-6 or IL-4 to the primary cultures led to a severalfold increase in IL-4 production and a concomitant decrease in IFNg production by the cells when restimulated. Significant IL-4 was produced upon restimulation even when no cytokines were added to the primary culture, and this IL-4 was eliminated either with anti-IL-6 antibodies or by using APC from IL-6 2 / 2 mice. Importantly, the ability of IL-6 to induce Th2 differentiation was blocked by antibodies to IL-4, implying that IL-6 acted by inducing IL-4 in the primary cultures, which in turn was the direct inducer of Th2 differentiation. In contrast, IL-4 was fully active on CD4 1 T cells from IL-6 2 / 2 mice, demonstrating that Th2 induction by IL-4 did not require IL-6. The evidence that IL-6 induces IL-4 production directly by the responding naive Th cells derives from experiments showing the induction of Th2 development in purified naive CD4 1 T cells by IL-6. These results suggest that IL-6 can rapidly induce sufficient IL-4 from these cells to lead to stable Th2 differentiation, although this was not directly demonstrated. It should also be noted that the cultures of naive T cells included whole splenocytes as the APC, and it was not ruled out that these were the source of IL-4. IL-6 is a prominent component of inflammatory and acutephase responses but has not previously been implicated in the preferential development of either Th2 or Th1 responses (reviewed in reference 4). Rincón et al. (3) suggest the interesting possibility that IL-6 is a key component in a link between innate immunity and Th2 responses, which parallels the connection between the macrophage/NK response to intracellular pathogens and Th1 induction. Not yet clear, however, are the specific conditions or pathogens that would favor Th2 over Th1 induction by this pathway. Furthermore, the relatively few published experiments with IL-6 2 / 2 mice do not give clear evidence of a defect in Th2 responses (5, 6). Several other recent studies have addressed the question of which cell population provides the early source of IL-4 in a Th2 response, and it is becoming evident that there are multiple answers to the question. The key cell involved in Th2 induction may depend on the route of immunization or infection or on the nature and concentration of the antigen. The cells that have drawn the most attention are NK1 1