Editorial: Jack of all trades? The versatility of IL-4 in CD8+ T cell polarity.

CD8 T cell function is required for proper immunity over a broad spectrum of activities, including but not limited to parasitic infection, tumorigenesis, and autoimmune disorders. These cells are triggered by antigen, but their function is influenced by various conditions, including cytokines. Analogous to Th1 and Th2 cells, CD8 Tc1 cells can produce Th1 type cytokines, such as IFN, and Tc2 cells can produce Th2 type cytokines, such as IL-4. These cytokines are critical for proper development of antitumor, antiviral, and allergic immunity. By contrast, CD8 T cells producing IL-10 have been found to be immune modulators in multiple experimental disease models [1, 2] but have also been suggested to be a specific differentiation state of CD8 T cells that have been stimulated excessively [3]. As is the case for CD4 T cells, different combinations of antigenic and cytokine stimulants can contribute to the different states of resultant effector CD8 T cells during the immune response. IL-4 is well known as a critical regulator of Th2 polarization in the differentiating CD4 T cells, particularly postantigenic priming. However the effect of IL-4 on CD8 T cells is still being appreciated. In this issue of Journal of Leukocyte Biology, Zhao et al. [4] use in vitro culture of CD8 T cells to show that IL-4, in combination with Con A, IL-2, and TCR triggering, potently induces a population of IL10-producing CD8 Tregs. They show that this process is dependent on the expression of the transcription factors Blimp-1 and Cdkn2a [4]. IL-10-producing CD8 T cells, induced via this route, can suppress IL-2/antigen-induced CD4 T cell proliferation in vitro in an IL-10and contact-dependent manner [4]. More importantly, these IL-10-producing CD8 T cells are able to dampen significantly the severity of 2,4,6-trinitrobenzenesulfonic acid-induced, Th1-mediated experimental murine colitis, suggesting an immunomodulatory function of this population in vivo. This function is similar to previous reported effects of IL-4 induction of IL10-producing CD8 T cells when cultured in the presence of IL-12 and TCR signals, and it would be useful to determine the stability of these cells in vivo. Those conditions can also suppress Th1 and Th2 cell proliferation and cytokine production, as well as the development of an experimental chronic graft-versus-host disease [5]. These findings suggest that induction of regulatory-like, IL-10-producing CD8 T cells (perhaps a cytotoxic Treg type 1 or CD8 Treg population analogous to the CD4 type I regulatory T cells [6]) is a significant property of the effects of IL-4 on CD8 T cells, dependent on the conditions. In contrast to these findings, several reports have also shown that IL-4 can induce innate memory-like CD8 T cell differentiation and act directly on CD8 T cells in vitro and in vivo to induce their ability to produce the Th1 cytokine IFN[7]. Although the molecular basis for this effect remains unclear, innate memory phenotype CD8 T cells derived via exposure to IL-4 can differentiate in the thymus from naive precursors, express memory markers, and carry preformed IFNmRNA that can be translated rapidly upon stimulation, suggesting properties of Tc1 cells [8, 9]. In addition, short-term in vitro exposure of naive CD8 T cells to IL-4 during TCR stimulation can induce potent induction of long-term memory in vivo, with enhanced potential for IFNand IL-4 production in the primed CD8 T cells (Fig. 1) [10]. Thus, IL-4 alone can induce naive CD8 T cells to become IFNproducers [7], or it can act in combination with other stimulants to induce other functional phenotypes (Fig. 1). Indeed, whereas IL-4, in combination with TCR triggering, induces primarily IFNproducers, it should be noted that a small proportion of these cells is also able to produce IL-10, which is enhanced further by IL-12 [5]. Interestingly, Zhao et al. [4] showed here that stimulating CD8 T cells with IL-4, along with Con A, IL-2, and TCR triggering, selectively enhances the development of IL-10-producing cells that do not produce IFN. These reports suggest that the effect of IL-4 is pleotropic and that it cannot only potentially regulate differentiation of Tc1 and Tc2 cells but also IL-10 and suggest that coinducers may modify the effects of IL-4 on CD8 T cells (Fig. 1). The versatility of IL-4 in acting in coordination with other stimuli on CD8 T cells suggests differential induction of