Good for Goose, but Not for Gander: IL-2 Interferes with Th17 Differentiation
2007; Cell Press; Volume: 26; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2007.03.001
ISSN1097-4180
Autores Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoIn this issue of Immunity, Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar examined the effects of interleukin-2 on differentiation of the T helper 17 (Th17) cells and found that this essential growth factor for all other T cell subsets blocks the development of Th17 T cells. In this issue of Immunity, Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar examined the effects of interleukin-2 on differentiation of the T helper 17 (Th17) cells and found that this essential growth factor for all other T cell subsets blocks the development of Th17 T cells. Interleukin 2 (IL-2) is one of the first cytokines identified, and it is firmly established as an important growth factor supporting a plethora of T cell functions. In vitro, IL-2 is obligatory for the growth of T helper 1 (Th1) or Th2 as well as CD8+ T cells. This function of IL-2 is less obvious in vivo because IL-2-deficient mice suffer from a hyperproliferative disorder. Nevertheless, IL-2 is essential for the acquisition of effector functions mediated by, for instance, interferon- γ (IFN-γ) or perforin. Thus, immunologists tend to add IL-2 into their T cell cultures on impulse and it is hardly even mentioned in the methods section of a paper anymore. However, as shown by Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar in this issue of Immunity, Th17 T cell differentiation is different and strongly discouraged by the presence of IL-2. Not only does the Th17 cell subset develop in response to the seemingly paradoxical combination of TGF-β, which is generally considered an anti-inflammatory cytokine, and IL-6, a proinflammatory cytokine (Bettelli et al., 2006Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K. Nature. 2006; 441: 235-238Crossref PubMed Scopus (5278) Google Scholar, Mangan et al., 2006Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Nature. 2006; 441: 231-234Crossref PubMed Scopus (2505) Google Scholar, Veldhoen et al., 2006Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (2891) Google Scholar), but as shown by Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar, Th17 differentiation is actively inhibited by IL-2. One could have guessed that Th17 must be less dependent on IL-2 because one of the actions of TGF-β is to block proliferation via its inhibitory action on IL-2 (Brabletz et al., 1993Brabletz T. Pfeuffer I. Schorr E. Siebelt F. Wirth T. Serfling E. Mol. Cell. Biol. 1993; 13: 1155-1162Crossref PubMed Google Scholar). However, Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar show that IL-2 is actively interfering with the differentiation of Th17 T cells. Addition of exogenous IL-2 reduces the proportion of Th17 in cultures of naive T cells driven by TGF-β and IL-6, whereas inversely, blocking of endogenous, autocrine IL-2 by the addition of neutralizing antibodies enhances Th17 differentiation. Furthermore, IL-2-deficient mice contain a substantially greater fraction of Th17 T cells, and in vitro stimulation of T cells from this strain results in higher proportions of IL-17-producing cells. Increased induction of Th17 T cells under conditions of IL-2 deficiency suggests that some of the autoimmune disorder of these mice may be due to the action of Th17 T cells, a possibility that needs to be explored further. A similar increase in Th17 T cells was found upon immunization of IL-2-deficient, Rag-deficient T cell receptor-transgenic mice, which harbor a monoclonal T cell population that is not activated without deliberate immunization. Such mice are not susceptible to the autoimmune disorder seen in polyclonal IL-2 deficient mice and the increased proportion of Th17 T cells that developed after immunization with cognate antigen are therefore unlikely to be the direct result of an autoimmune state. The main rationale for assessing the role of IL-2 in this paper was the reported dichotomy of Th17 cell versus regulatory T (Treg) cell differentiation. The initial finding of a seemingly reciprocal activation of Treg versus Th17 cells was based on results showing that in vitro stimulation of naive T cells in the presence of TGF-β induces Foxp3-expressing Treg cells, unless IL-6 is added, in which case it supports Th17 cell differentiation (Bettelli et al., 2006Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K. Nature. 2006; 441: 235-238Crossref PubMed Scopus (5278) Google Scholar). Although it remains dubious whether such a pathway of Treg cell differentiation plays a significant role under physiological conditions in vivo, where T cell activation by antigen-presenting dendritic cells is most likely always accompanied by supply of IL-6, there is no doubt that IL-2 plays an obligatory role as a survival factor for natural Treg cell generated in the thymus. Thus, the study by Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar provides an alternative and possibly more physiologically relevant example for Th17-Treg cell dichotomy. The mechanisms underlying the blockade of Th17 differentiation by IL-2 are not entirely clear, although Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar offer a variety of possibilities. STAT5, which is activated by IL-2 and other common γ chain (γc) cytokines, appears to be a negative regulator of Th17 differentiation in contrast to STAT3, which is activated by both IL-6 and IL-23 and positively regulates RORγt expression and Th17 cell development (see Figure 1). STAT5-deficient mice harbor an increased proportion of Th17 cells, and in vitro polarization of thymocytes (devoid of prepolarized Th17 cells) results in enhanced Th17 differentiation. The addition of IL-2 to cultures of naive T cells under Th17-polarizing conditions reduced the expression of RORγt, and this paralleled the decrease in Th17 cell development. Thus, despite the fact that STAT5-deficient T cells seem to produce 10-fold more IL-2 than T cells from wild-type mice, as shown in a previous paper by this group (Villarino et al., 2007Villarino A.V. Tato C.M. Stumhofer J.S. Yao Z. Cui Y.K. Hennighausen L. O'Shea J.J. Hunter C.A. J. Exp. Med. 2007; 204: 65-71Crossref Scopus (95) Google Scholar), the absence of STAT5 precludes an inhibitory effect on Th17 development. Furthermore, Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar identified STAT5-binding sites in the IL-17 promoter and suggest that STAT5 might attenuate IL-17 production by direct binding to the IL-17 promoter. This, however, is not the same as inhibiting Th17 cell differentiation. IL-17 has no positive feedback effect on the generation of the Th17 lineage, and merely inhibiting cytokine production would therefore not block their differentiation. In contrast, it is not known whether STAT5-mediated effects influence the amounts of IL-17 produced by fully differentiated Th17 cells. This study shows increased amounts of IL-17 in the serum of STAT5-deficient mice, which is presumably due to increased Th17 development in such mice. However, the possibility that STAT5 signaling via IL-2 might reduce IL-17 production by established Th17 effector cells was not explored but might be of relevance in autoimmunity where the amounts of IL-17 may determine the degree of pathology. Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Immunity. 2007; 26 (this issue): 371-381Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar clearly establish the negative role of IL-2 signaling for Th17 cell development, an important contribution that may hopefully resolve residual difficulties still experienced in attempts to generate Th17 cells in vitro. This applies especially to the human system, where doubts are circulating whether human Th17 development follows the same rule as that of mouse Th17 development. However, what remains unclear is the physiological context in vivo in which the IL-2-mediated Treg versus Th17 paradigm is applicable. The coculture of Treg and naive T cells under conditions that mimic an inflammatory stimulus, e.g., in the presence of IL-6, strongly supports Th17 generation (Veldhoen et al., 2006Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (2891) Google Scholar). Given the potential problem that Th17 cells could cause autoimmunity, such a scenario is clearly undesirable in vivo. Presumably, Treg cells are not in the vicinity when a T cell response is initiated by contact with antigen presenting dendritic cells. However, Treg cells are notorious for scavenging IL-2 from responder cells and inhibiting their IL-2 transcription (Barthlott et al., 2005Barthlott T. Moncrieffe H. Veldhoen M. Atkins C.J. Christensen J. O'Garra A. Stockinger B. Int. Immunol. 2005; 17: 279-288Crossref PubMed Scopus (151) Google Scholar, Thornton and Shevach, 1998Thornton A.M. Shevach E.M. J. Exp. Med. 1998; 188: 287-296Crossref PubMed Scopus (2119) Google Scholar), a scenario that would seem ideal for the differentiation toward the Th17 program. Thus, although Treg clearly dampen Th1- or Th2-mediated pathology, we are left with the tantalizing question of whether Treg cells, rather than controlling Th17 cells, actually promote Th17 development as well as their effector function by scavenging their negative regulator IL-2. Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell GenerationLaurence et al.ImmunityMarch 23, 2007In BriefRecent work has identified a new subset of effector T cells that produces interleukin (IL)-17 known as T helper 17 (Th17) cells, which is involved in the pathophysiology of inflammatory diseases and is thought to be developmentally related to regulatory T (Treg) cells. Because of its importance for Treg cells, we examined the role of IL-2 in Th17 generation and demonstrate that a previously unrecognized aspect of IL-2 function is to constrain IL-17 production. Genetic deletion or antibody blockade of IL-2 promoted differentiation of the Th17 cell subset. Full-Text PDF Open Archive
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