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T Helper Cell Differentiation: Understanding the Needs of Hierarchy

Thomas Weichhart1,* and Marcus D. Sa¨ emann1,* 1Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University Vienna, Wa¨ hringer Gu¨ rtel 18-20, A-1090 Vienna, Austria *Correspondence: [email protected] (T.W.), [email protected] (M.D.S.) DOI 10.1016/j.immuni.2010.06.008

In this issue of , Lee et al. (2010) demonstrate that the mammalian Target of Rapamycin Complex 2 promotes the differentiation of T helper 1 (Th1) cells via the kinase Akt, whereas it independently fosters Th2 cell generation via another kinase, PKC-q.

Regulation of the manifold and flexible mTOR is a critical regulator of memory Akt S473 was defective after stimulation requirements of an efficient immune CD8+ generation as well as inflam- with CD3 and CD28 mAb, whereas response to eliminate dangerous micro- matory responses in myeloid -pre- mTORC1-mediated phosphorylation of bes depends on a delicate balance of senting cells (Araki et al., 2009; Weichhart S6K1 was intact. Functionally, however, diverse T helper (Th) cell subsets (Zhu et al., 2008). mTOR is the core component it was found that Rictor-deficient CD4+ et al., 2010). Hence, naive CD4+ Th cells of mTORC1 (mTOR complex 1), which is T cells were unable to differentiate into differentiate into polarized effector Th composed by the adaptor Raptor, both Th1 or Th2 cells in vitro, demon- cell subsets depending on the whereas Rictor and Sin1 classify strating that mTORC2 is vital for Th1 and milieu. Th1 cells can be gener- mTORC2. mTORC1 and mTORC2 are Th2 cell differentiation. The lineage-deter- ated by exposure to like IL-12 a coupled part of a complex signaling mining transcription factors for Th1 and and IFN-g to defend and intracel- pathway that integrates various environ- Th2 development, T-bet and GATA3, lular , whereas IL-4, IL-5, and IL- mental cues including growth factors, respectively, were also reduced in the 13 induce Th2 cells to promote - cytokines, and nutrients. mTORC2 phos- absence of Rictor. These data were mediated immunity and defend parasitic phorylates the kinase Akt on serine 473, confirmed indirectly by measuring Th infections. The minimal cytokine cocktail whereas the PI3-kinase induces Akt cell-mediated responses in their IL-6 plus TGF-b enables the development phosphorylation at threonine 308 to direct mice in vivo; Th1 and Th2 cell-dependent of IL-17 producing Th17 cells that are mTORC1 activation via Rheb, a RAS-like antibody production (IgG2a, IgG3 and associated with protection against extra- GTPase. Rapamycin, the prototypical IgG1, IgE, respectively) was markedly cellular bacteria as well as . inhibitor of mTORC1, has been tradition- reduced after the appropriate immuniza- Alternatively, naive CD4+ T cells may ally employed to study the impact of tion. In contrast, Th17 cell differentiation differentiate into induced regulatory T mTOR on the development, activation, was not compromised in Rictor-deficient (iTreg) cells after stimulation with TGF-b and proliferation of Th cells. Recently, cells in vitro, indicating that mTORC1 and IL-2 that are vital for the induction mTOR-deficient Th cells have been promotes Th17 cell differentiation, and maintenance of . shown that are unable to differentiate whereas mTORC2 critically determines Although the respective cytokine milieu into Th1, Th2, and Th17 cells, but prefer- Th1 and Th2 cell lineage commitment. and the transcription factors that control entially develop into iTreg cells (Delgoffe However, caution is warranted from Th cell differentiation have been charac- et al., 2009). Because mTOR deficiency a straightforward interpretation, because terized in considerable detail, the intracel- wipes out both mTORC1 and mTORC2, in their current study Lee et al. (2010) lular pathways that dictate the balance it is unclear so far which mTOR complex induced Th17 cell differentiation by exog- between the individual effector lineages is critical for Th cell lineage commitment. enous TGF-b, IL-6, and IL-23, whereas in are still incompletely understood. In this Lee et al. (2010) now directly addressed the previous study only TGF-b and IL-6 issue of Immunity, Lee et al. (2010) this important question by describing the were used (Delgoffe et al., 2009). Hence, demonstrate that mTORC2 is centrally generation of mice that selectively lack mTORC2 might be still important for positioned as a Th cell signaling diversifier the essential mTORC2 subunit Rictor in Th17 cell differentiation under conditions to specifically induce the subsequent T cells via the cre-lox system. Deleting without the help of IL-23. differentiation of Th1 and Th2 cells via Rictor by this approach in As outlined, mTOR-deficient CD4+ the two kinases Akt and PKC-q, respec- after the double-positive stage T cells preferentially differentiate into an tively. did not impede general CD4+ T cell devel- iTreg cell during nonpolarizing mTOR is a signaling kinase that affects opment and also did not influence the and Th1 cell-polarizing conditions in vitro broad aspects of cellular functions generation of natural Treg cells. Analyzing and in vivo, whereas Rheb-deficient including immunity, metabolism, growth, the activity of mTORC1 and mTORC2 in T cells corresponding to cells with survival, and aging (Weichhart and Sae- Rictor-deficient mature CD4+ T cells, mTORC1 absence did not recapitulate mann, 2009). In the , mTORC2-dependent phosphorylation of these effects, implying that mTORC2

Immunity 32, June 25, 2010 ª2010 Elsevier Inc. 727 Immunity Previews

that rapamycin can further enhance tial for Th2 cell priming (Marsland and CD3 CD28 FoxP3 expression even in Rictor-deficient Kopf, 2008), Lee et al. (2010) investigated CD4+ T cells. Alternatively, Rictor or Rheb whether PKC-q might be involved in might influence iTreg cell generation also mTORC2-dependent Th cell differentia- in an mTORC2- or mTORC1-independent tion. Reconstitution of Rictor-deficient manner, respectively. T cells with constitutive active PKC-q ? How does mTORC2 promote both Th1 specifically reverted the Th2 but not the mTORC2 mTORC1 and Th2 cell differentiation and prolifera- Th1 cell defect. Along these lines, the tion? Previous studies with rapamycin mutant PKC-q reestablished GATA3 suggested that mTORC1 is vital for effi- expression during Th2 cell differentiation, θ Akt PKC- cient cell cycle progression of CD4+ but did not influence T-bet under Th1 cell- ? T cells by blocking G1-S transition (Song priming conditions. Moreover, because et al., 2007). In the current study, Lee the important transcription factor NF-kB T-bet GATA-3 et al. (2010) found that Rictor-deficient has been shown to be activated by CD4+ T cells proliferated poorly in PKC-q to drive Th2 cell differentiation, response to CD3 and CD28, because of the effects of Rictor deficiency on NF-kB a block at the G1-S phase. Hence, either were analyzed. It was shown that CD3- both mTORC1 and mTORC2 are impor- and CD28-induced NF-kB activity was tant for efficient cell cycle progression, strongly diminished in Rictor-deficient iTreg + Th1 or the well-known defect in cell-cycle CD4 T cells, but could be rescued by progression upon treatment with rapamy- overexpression of the PKC-q mutant. Th17 Th2 cin is attributable to a rapamycin-sensi- These results suggest that mTORC2 tive mTORC2 activity. Indeed, Lee et al. promotes Th1 cell differentiation via Akt, (2010) showed that rapamycin also whereas mTORC2 drives the generation + Figure 1. Th1 and Th2 Cell Differentiation affected mTORC2 activity in CD4 T cells, of Th2 cells via PKC-q (Figure 1). Is Controlled by mTORC2 via Akt and PKC-q, a phenomenon that has also been recog- A major discrepancy between the Respectively nized in other cell types. present results and previous data with mTOR is contained in two protein complexes in the + CD4+ T cell, mTORC1 and mTORC2, both of which The most intriguing set of data of the mTOR-deficient CD4 T cells resides in are activated after CD3 and CD28 engagement. current study is the finding that mTORC2 the conclusion about the critical involve- mTORC2 directly phosphorylates the protein splits its function to promote both Th1 ment of STATs that mediate the expression kinase Akt to induce expression of the Th1 cell- determining transcription factor T-bet and hence and Th2 cell differentiation to distinct of the lineage-specific transcription factors Th1 cell differentiation. mTORC2 also activates protein kinases. Because Akt is the best- for Th cell differentiation. Whereas mTOR- PKC-q to upregulate the expression of GATA-3, characterized kinase downstream of deficient cells display a decrease in STAT4 the central Th2 cell-determining transcription mTORC2, the authors reconstituted Ric- and STAT3 activation, Rictor-deficient factor in CD4+ T cells. However, a role of mTORC1 + in Th1 and Th2 cell generation cannot be excluded tor-deficient CD4 T cells with a constitu- T cells showed completely unimpaired so far. In addition, mTORC1 and mTORC2 nega- tively active Akt mutant and monitored the STAT activation. Moreover, rapamycin tively regulate iTreg cell development under certain Th1 and Th2 cell differentiation potential: failed to block STAT4 and STAT3 phos- conditions, whereas mTORC1 seems to be exclu- sively dominant for Th17 cell differentiation. the Akt mutant rescued the Th1 cell differ- phorylation in the experiments of Lee Some unidentified factors and/or the initial entiation defect, but it was ineffective in et al. (2010). There remains the possibility signaling strength might mediate a differential acti- restoring Th2 cell differentiation. In agree- that rapamycin might not completely block vation signal to mTORC1 versus mTORC2 influ- encing effector Th cell differentiation. ment, active Akt specifically rescued mTORC1 signaling. Alternatively, different expression of the transcription factor T- experimental setups, e.g., primary cellular bet but not GATA3. Phosphorylation of activation versus preactivated cells, might might prevent iTreg cell conversion (Del- the negative regulator FoxO1 by Akt explain this inconsistency. goffe et al., 2009). In seeming contrast, inhibits its activity and thereby enhances Interestingly, the Th cell-priming condi- Lee et al. (2010) showed that mTORC2 T cell proliferation as well as T-bet expres- tions only modestly influence the CD3- deficiency induced by loss of Rictor did sion. Indeed, Rictor-deficient CD4+ T cells and CD28-induced phosphorylation of enhance iTreg cell generation as showed reduced phosphorylation of S6K1, Akt S473, and PKC-q, e.g., the rela- measured by the expression of FoxP3 FoxO1 compared to WT cells. Because tive activation of mTORC1 versus under neutral conditions in the presence all three Akt isoforms are expressed in mTORC2 and of Akt versus PKC-q after of TGF-b but not without TGF-b or under ab T , it is unclear which iso- 4 days of differentiation, indicating that Th1 and Th2 cell-driving conditions. form is critical downstream of mTORC2 the mTOR pathway might be an intrinsic Although the experimental setup of Del- for Th1 cell generation. Nevertheless, regulator of Th cell differentiation inde- goffe et al. (2009) and Lee et al. (2010) these data perfectly fit in a model where pendent of environmental cues (e.g., IL- are not directly comparable, one possible Akt acts as an amplifier of Th1 cell differ- 12 or IL-4) that would favor Th1 or Th2 explanation might be that both mTORC1 entiation (Arimura et al., 2004). Recently, cell generation, respectively. However, and mTORC2 are essential for controlling mTORC2 has been implicated in acti- various alternative scenarios are conceiv- iTreg cell expansion. This view is sup- vating several PKC kinases (Ikenoue able: the time point to assess mTOR acti- ported by the present study showing et al., 2008) and because PKC-q is essen- vation might have been too late or the

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small differences observed were suffi- REFERENCES Boothby, M. (2010). Immunity 32, this issue, cient to influence Th cell differentiation 743–753. via altered mTORC1-mTORC2 and Akt- Araki, K., Turner, A.P., Shaffer, V.O., Gangappa, S., Keller, S.A., Bachmann, M.F., Larsen, C.P., and Marsland, B.J., and Kopf, M. (2008). Trends Immu- PKC-q activation. Moreover, the strength Ahmed, R. (2009). 460, 108–112. nol. 29, 179–185. of the CD3 and CD28 signal might be important for selective mTOR pathway Arimura, Y., Shiroki, F., Kuwahara, S., Kato, H., Di- Song, J., Salek-Ardakani, S., So, T., and Croft, M. anzani, U., Uchiyama, T., and Yagi, J. (2004). J. (2007). Nat. Immunol. 8, 64–73. activation or other environmental factors Biol. Chem. 279, 11408–11416. influence the Th cell differentiation Weichhart, T., and Saemann, M.D. (2009). Trends process via mTOR signaling. Finally, as Delgoffe, G.M., Kole, T.P., Zheng, Y., Zarek, P.E., Immunol. 30, 218–226. nutrients such as amino acids or glucose Matthews, K.L., Xiao, B., Worley, P.F., Kozma, S.C., and Powell, J.D. (2009). Immunity 30, directly control the activation of the 832–844. Weichhart, T., Costantino, G., Poglitsch, M., Ros- mTOR pathway, it is tempting to hypothe- ner, M., Zeyda, M., Stuhlmeier, K.M., Kolbe, T., size that nutrients do not merely control Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., and Stulnig, T.M., Horl, W.H., Hengstschlager, M., et al. (2008). Immunity 29, 565–577. T cell proliferation but that the nutritional Guan, K.L. (2008). EMBO J. 27, 1919–1931. status might also control Th cell differenti- Lee, K., Gudapati, P., Dragovic, S., Spencer, C., Zhu, J., Yamane, H., and Paul, W.E. (2010). Annu. ation via the mTOR signaling complex. Joyce, S., Killeen, N., Magnuson, M.A., and Rev. Immunol. 28, 445–489.

Only the Strong Survive

Andreas Villunger1,* 1Division of Developmental , Biocenter, Innsbruck Medical University, Innsbruck, Austria *Correspondence: [email protected] DOI 10.1016/j.immuni.2010.06.010

Whether is relevant for interclonal competition of T cells after antigen encounter has remained uncertain. In this issue of Immunity, Wensveen et al. (2010) establish a critical role for the proapoptotic BH3-only protein Noxa in this selection process.

Apoptosis plays a critical role in the selec- known as Bcl-2 interacting mediator of TCR ligation in human naive T cells and tion of functionally competent immune cell death (Bim), a BH3-only protein that repression of protein expression by cells. During development, belonging to one proapoptotic subclass RNA interference provided a selective apoptosis eliminates cells that lack antigen of the Bcl-2 family with at least eight advantage in cell-growth competition expression in a process known as members, has been shown to be critical experiments to Jurkat T acute lympho- ‘‘death by neglect,’’ but also mediates the for this selection process (Fischer et al., blastic leukemia and primary activated death of cells that express potentially 2007). Bim is also critical for T cell deletion T cells under conditions of glucose limita- autoreactive antigen receptors during after antigen clearance in which other BH3- tion (Alves et al., 2006). Others observed ‘‘negative selection,’’ critical for generating only , such as Puma or Noxa (also that Noxa limits the lifespan of memory tolerance. Both types of cell death are known as Pmaip1), can play auxiliary roles T cells (Yamashita et al., 2008) or, together controlled by Bcell lymphoma-2 (Bcl-2) (Bauer et al., 2006). Notably, the latter two with Bim, restricts survival of NK cells family proteins that fall into pro- and antia- proteins have been identified as direct in the absence of their major survival poptotic groups and that integrate different target genes of the tumor suppressor p53, cytokine, IL-15 (Huntington et al., 2007). formsofcellstressaswellasdevelop- activated in order to execute apoptosis Performing a consequent follow up of mental cues at the level of mitochondria in induced by DNA damage. However, the their initial observations, Wensveen et al. order to preserve cell survival or initiate physiological role of Noxa has remained (2010) now provide compelling evidence cell death (Strasser, 2005). Apoptosis has rather obscure, given that its loss confers that Noxa limits the survival of T cell clones also been recognized as critical for affinity only mild resistance to DNA-damage- that express low-affinity TCRs during maturationofBcellscompeting foralimited induced apoptosis, and only in selected interclonal competition, a process that amount of antigen and supporting cyto- cell types (Ploner et al., 2008). leads to the outgrowth of the ‘‘best-fit’’ kines in reactions. This One of the first hints that Noxa can high-avidity T cellclones from a large panel process secures that only clones ex- act outside the DNA-damage response of antigen-reactive naive T cells during pressing B cell receptors with the highest came from the demonstration that its antigenic challenge (Malherbe et al., 2004; affinity are able to thrive. Bcl2l11, also expression was induced in response to Zehn et al., 2009).

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