The discovery of the dichotomy between T helper 1 (TH1) cells and TH2 cells by Timothy Mosmann and Robert Coffman in 1986 was a major breakthrough for the understanding of how cellular and humoral immune responses are orchestrated. The next big question in the field concerned the factors that induce TH1 cell or TH2 cell differentiation. Two studies from the groups of Giorgio Trinchieri (Kobayashi et al., 1989) and Anne O’Garra (Fiorentino et al., 1991) were enlightening in this regard.
Kobayashi et al. reported the biochemical characterization of natural killer (NK) cell stimulatory factor (now known as IL-12), a cytokine that induces production of the TH1 cell cytokine IFNγ by NK cells and T cells. Soon after, Fiorentino et al. showed that IL-10 antagonizes the development of TH1 cells by suppressing the synthesis of pro-inflammatory cytokines by antigen-presenting cells (APCs). These two findings were put together by a study showing that IL-12 produced by APCs directs the differentiation of TH1 cells and that this is inhibited by IL-10 (Hsieh et al., 1993).
Parasite infections, which cause chronic T cell stimulation, became great models to study the differentiation and functions of polarized TH cells, as well as immunoregulatory mechanisms (Sher & Coffman, 1992). The IL-12–IFNγ axis and the antagonist IL-10 were defined as biomarkers of host resistance and susceptibility to Leishmania major and other infectious disease models. It became clear that IL-12 is an ‘adjuvant’ cytokine that drives the development of protective T cell-mediated immunity in vaccination protocols. Studies with helminths helped us to understand the basis of TH2 cell responses and why antigen exposure through the IL-10-rich intestinal mucosa or airways is often accompanied by a TH2 cell response. Later studies with Toxoplasma gondii determined that a primary role of IL-10 is to prevent excessive immune responses and consequent pathology. Today, we know that many of the functions of regulatory T (Treg) cells are mediated by IL-10.
These studies had broad implications in the field of immunology. They served as a paradigm to understand how different microorganisms and tissue environments influence TH cell differentiation, the functional diversity of CD4+ T cell subsets, the basis of vaccine adjuvants and the function of Treg cells. These findings also had major effects on translational medicine by providing insights for clinical immunology, vaccinology and immunotherapy.
Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989)
Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991)
Hsieh, C. S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993)
Sher, A. & Coffman, R. L. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu. Rev. Immunol. 10, 385–409 (1992)
The author declares no competing interests.
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Gazzinelli, R. Seeing through the parasites’ eyes. Nat Rev Immunol 19, 137 (2019). https://doi.org/10.1038/s41577-019-0129-4