The 1980s witnessed the identification of numerous secreted proteins that participate in intercellular communication. For immunologists, much attention was paid to the soluble proteins produced specifically by activated lymphocytes or myeloid cells. These factors belong to several cytokine families that, unlike Igs, convey antigenically nonspecific signals to orchestrate immune or inflammatory responses. Rarely included in this category was transforming growth factor-β (TGF-β), which originally had been identified as a molecule produced by virally transformed cells to promote anchorage-independent growth of connective tissue cells (1). Later studies revealed that in addition to tumor cell lines, many normal tissues such as liver, heart, kidney, and platelets expressed TGF-β (2). Such a wide distribution of TGF-β in the body was in line with its pleiotropic functions in the control of embryonic development, tissue maintenance, and carcinogenesis.

Then, in 1986, came the study by John Kehrl, Anthony Fauci, and colleagues (3) published in The Journal of Experimental Medicine, which reported for the first time that TGF-β is not only produced by T cells, but also regulates T cell responses, and thus identified a role for TGF-β regulation of immune responses. This Pillars of Immunology article opened up a field that has impacted almost all aspects of T cell biology research to date (4). In fact, TGF-β remains one of the most fascinating and biologically important proteins in the immune system (5).

Most of the cytokine research during the 1980s focused on molecules that promoted growth and effector functions of murine and human lymphocytes (6). For instance, IL-2 was identified as a potent growth factor that binds to the high-affinity IL-2 receptor expressed on mitogen-activated T cells and induces cell cycle progression (7). In search of a potential function for TGF-β in T cells, Kehrl et al. used TGF-β purified from human platelets and explored its effect on IL-2–dependent proliferation of Con A–activated human tonsil T cells. They found that TGF-β inhibits IL-2–induced cell cycle progression as well as cell surface expression of the IL-2 receptor and the transferrin receptor, molecules associated with T cell proliferation. These observations demonstrated an immunoregulatory role for TGF-β, making it one of a kind among the cytokines studied at the time.

Although the growth-inhibitory property of TGF-β had previously been observed in epithelial cells (8), the discovery of the suppressive function of TGF-β on T cells had special implications for understanding one of the most fundamental questions in immunology, immune tolerance. A major tenet of modern immunology is Burnet’s clonal selection theory, in which clonal deletion of developing lymphocytes was considered the principal mechanism to wean out self-reactivity. Nevertheless, we now know that central tolerance is no more than one of the many checkpoints that ensure the discrimination of self from non-self (9). Indeed, autoreactive T lymphocytes are readily apparent in the mature T cell repertoire and must be kept in check by peripheral immune tolerance mechanisms. In line with the suppressive activity of TGF-β on T cells in vitro, studies of TGF-β1–deficient mice in the 1990s and T cell–specific TGF-β receptor knockouts in the 2000s showed a crucial function for TGF-β in the control of T cell tolerance (1013), which has recently been demonstrated to be distinct from thymic deletion of autoreactive T cells (14).

Another interesting observation Kehrl et al. made was that TGF-β inhibition of T cell proliferation was diminished at higher IL-2 concentrations, implying that TGF-β–mediated suppression is not a hardwired process, but is modulated by the signaling strength of other cytokines. In fact, recent studies have revealed important functions for TGF-β in inducing the differentiation of peripheral regulatory T cells in concert with high doses of IL-2 (15), and even IL-17–producing helper T cells in the presence of IL-6 (16, 17). These original and subsequent studies have established TGF-β as one of the most versatile regulatory cytokines in T cell biology.

Unlike hormones, which circulate through the body to control target cells at distant sites, cytokines chiefly act locally via the autocrine or paracrine route on cells within a tissue, like neurotransmitters. Having observed that exogenous TGF-β could modulate T cell proliferation, Kehrl et al. explored the possibility that T cells themselves might produce the cytokine. Taking advantage of the cloned human Tgfb1 gene, Northern blot experiments were performed on RNA isolated from T cells stimulated by PHA. Indeed, Tgfb1 message was readily detected in PHA-activated T cells. Importantly, TGF-β1 protein was secreted into the T cell culture supernatant, revealing that TGF-β1 was a bona fide lymphokine, that is, a cytokine produced by lymphocytes. However, the definitive function of T cell–produced TGF-β1 was not revealed until the generation of T cell–specific TGF-β1–deficient mice. These studies showed that T cell–derived TGF-β1 controls T cell homeostasis and differentiation through autocrine and paracrine mechanisms in the steady-state and in diseases such as cancer (1820), demonstrating a “close bonding” between TGF-β1 and T cells.

The principle of TGF-β control of T cells put forth in the pioneering study by Kehrl et al. stands three decades later, and it has been further extended in murine models. The rich immunology brought forth by TGF-β research raises the intriguing question of why the TGF-β pathway occupies such an important position in the regulatory network of adaptive immune responses. By no means is TGF-β a traditional lymphokine or cytokine. In fact, the ancient origin, ubiquitous expression, and pleiotropic activities of TGF-β make it a prototypical multifunctional molecule involved in coupling cellular responses to environmental or cell-intrinsic changes. Perhaps TGF-β signaling has been strategically co-opted during evolution to ensure the functionality of lymphocytes whose development and differentiation are amalgamated with the decoding of various intercellular communication signals. Future studies will reveal the crosstalk between TGF-β and other T cell regulatory molecules and explore the possibility of targeting TGF-β for the treatment of immune disorders.

I thank Dr. Pamela Fink for the invitation to write this commentary and Dr. Soyoung Oh for critical reading of the manuscript.

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The author has no financial conflicts of interest.