RESEARCH HIGHLIGHTS

T-CELL DEVELOPMENT from reaching or progressing past the positive-selection checkpoint. So, IAN-family members are novel Life and death with the IAN family TCR-responsive that crucially and differentially regulate the survival and death of Immune-associated nucleotide-binding proteins mechanisms that regulate these selection thymocytes. In subsequent experiments, IAN1 (IANs; also known as GIMAPs) constitute a family processes. When examining the transcriptional was found to associate selectively with the pro- of GTP-binding proteins that are expressed by profile of mouse thymocytes with various apoptotic BCL-2 (B-cell lymphoma 2)-family vertebrate immune cells. Until recently, little has developmental characteristics, they found member BAX (BCL-2-associated X ), been known about the function of these proteins. that the IAN-family proteins IAN1 and IAN4 are whereas IAN4 and IAN5 were found to associate Now, a report in PLoS Biology shows that IAN1, strongly upregulated by thymocytes that have with anti-apoptotic BCL-2-family members,

IAN4 and IAN5 are crucial regulators of T-cell undergone positive selection (that is, in cells that including BCL-2 and BCL-XL. These findings development in the . have progressed from the double-positive (DP) indicate that IANs might exert their functions by Developing T cells must pass through a series to the single-positive stage of development). They relaying signals that regulate from the of checkpoints in the thymus. These include confirmed this finding using quantitative real- TCR to BCL-2-family members, and this improves positive selection and negative selection, both of time PCR and additionally showed that IAN5 is our understanding of the mechanism by which which depend on T-cell (TCR) signalling also upregulated at this stage. However, enforced TCR signalling influences the fate of thymocytes. and which result, respectively, in the survival overexpression of IAN1 (but not IAN4 or IAN5) at Davina Dadley-Moore of thymocytes that express a functional TCR an early stage of development (in double-negative and in the apoptotic death of thymocytes that thymocytes) was found to result in apoptosis at ORIGINAL RESEARCH PAPER Nitta, T. et al. IAN family strongly recognize ligand. Yousuke Takahama the DP stage, whereas inhibition of endogenous critically regulates survival and development of T . PLoS Biol. 4, e103 (2006) and colleagues set out to study the molecular expression of IAN4 or IAN5 (but not IAN1) blocked

T CELLS T helper 1 (TH1)-associated IL-12, IL-23 and IFNγ

and the TH2-associated De novo generation of IL-17-producing T cells IL-4, resulted in the differentiation of IL-17-producing T cells. Inclusion The mechanism involved in the identified as the key component in of TGFβ-specific anti bodies inhibited de novo differentiation of inter- this differentiation process. Blocking this differentiation, indicating that, leukin-17 (IL-17)-producing T cells TGFβ, but not the T -cell-associ- in addition to TGFβ produced by a unique Reg + from naive CD4 T cells is not fully ated cytokine IL-10, with neutralizing TReg cells, LPS-stimulated DCs can understood, but it has been suggested balance of suppressed the generation produce TGFβ, albeit in amounts that IL-23 might be involved. Now, pro- and anti- of IL-17-producing T cells. The that cannot support IL-17-producing

new research published in inflammatory TReg cells could also be replaced in T-cell differentiation without β highlights a pivotal role for transform- cytokines is the co-culture by addition of TGF , further blockade of cytokines that ing growth factor-β (TGFβ), together highlighting the crucial role of this promote the differentiation of the with the pro- necessary for cytokine in the differentiation of other T-cell subsets. IL-6, in the generation of these cells. the de novo IL-7-producing T cells. Therefore, TGFβ, together with The naturally occurring generation This study also showed that in IL-6, is essential for the de novo differ- CD4+CD25+ regulatory T (T )-cell addition to TGFβ, a DC-derived entiation of IL-17-producing T cells Reg of IL-17- subset — which can prevent immune factor is required, as the generation from naive CD4+ T cells. It seems that, pathology through the suppression producing of IL-17-producing T cells did not in addition to the suppressive role of β of potentially pathogenic T cells T cells occur in the absence of DCs. The TGF on TH1, and TH2-cell differenti- — suppress proliferation and IL-2 authors identified the cytokine IL-6 ation, this cytokine might also have a production by naive CD4+ T cells as this essential mediator. Blocking of more direct role in the differentiation in vitro. However, Stockinger and IL-6 suppressed the development of IL-17-producing T cells. So, this colleagues show that in the presence of IL-17-producing T cells, whereas study shows that a unique balance of of an inflammatory stimulus, such as tumour-necrosis factor (TNF) and pro- and anti-inflammatory cytokines β (LPS), TReg cells IL-1 further augmented this differ- is necessary for the de novo generation do not suppress T-cell proliferation entiation. Interestingly, inhibition of of IL-17-producing T cells. but still retain the ability to suppress IL-23 did not affect the differentiation Olive Leavy the production of IL-2 and also of these cells, indicating that this -γ (IFNγ). Interestingly, co- cytokine probably does not have ORIGINAL RESEARCH PAPER Veldhoen, M., + Hocking, R. J., Atkins, C. J., Locksley, R. M. & culture of TReg cells with naive CD4 a role in the de novo generation of Stockinger, B. TGFβ in the context of an T cells, in the presence of dendritic IL-17-producing T cells, although it is inflammatory cytokine milieu supports de novo cells (DCs) and LPS, results in the an important factor for their survival differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006) induction of IL-17-producing T cells. and expansion. FUTHER READING Dong, C. Diversification of TGFβ, an immunosuppressive Co-culture of naive CD4+ T cells T-helper-cell lineages: finding the family root cytokine that is produced by various with DCs and LPS in the presence of IL-17-producing cells. Rev. Immunol. 17 Mar 2006 (doi:10.1038/nri1807) cell types including TReg cells, was of antibodies specific for the

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