Ubiquitin switch

Tumor necrosis factor receptor 1 (TNFR1) can trigger survival or death, but the mechanisms that determine the outcome of TNFR1 stimulation are not known. In Current Biology, Ting and colleagues designate ubiquitination of RIP1, an adaptor in the TNFR1 signaling pathway, as a molecular 'pivot point' on which the balance between life and death rests. RIP1-deficient Jurkat cells reconstituted with a mutant RIP1 protein lacking Lys377, to which Lys63-linked polyubiquitin chains are attached, are more susceptible to TNFR1-induced apoptosis and have more processing of procaspase 8 than do Jurkat cells expressing wild-type RIP1. Early TNFR1-induced cell death independent of transcription factor NF-κB may depend on binding of RIP1 to procaspase 8. Mutant RIP1 binds more caspase 8 than does wild-type RIP1, suggesting that RIP1 ubiquitination determines whether TNFR1 signaling suppresses or promotes apoptosis. Whether ubiquitination enhances RIP1–procaspase 8 binding by influencing RIP1 intracellular localization or conformation remains to be determined. CB

Curr. Biol. 17, 418–424 (2007)

Blunting T H -17

IL-17-producing T helper cells (TH-17 cells) are mediators of substantial immune pathology in some autoimmune disorders, but how these cells can escape suppression imposed by regulatory T cells (Treg cells) remains unknown. In Immunity, Laurence et al. show that IL-2 blocks the polarization of naive CD4+ T cells to TH-17 cells. Loss of IL-2 or its 'downstream' signaling transactivator STAT5 leads to enhanced production of IL-17 and more TH-17 cells. Conversely, loss of IL-6- or IL-23-mediated activation of STAT3 (or STAT3 deficiency in mice) leads to more Treg cells. These results suggest that a dichotomy between STAT3 and STAT5 signals profoundly influences whether a given CD4+ T cell develops a regulatory phenotype or a potentially autoaggressive phenotype. Likewise, they may explain the earlier conundrum of how loss of IL-2 or its receptor leads to rapid lymphoproliferative autoimmune disease. LAD

Immunity 26, 371–381 (2007)

S1P sources

Lymphocytes lacking the sphingosine 1-phosphate type 1 receptor S1P1 fail to move from lymphoid organs to the blood and lymph, which have relatively high concentrations of S1P. In Science, Cyster and coworkers demonstrate that S1P in blood and lymph is produced by distinct sources. Mice lacking sphingosine kinases required for S1P production have a dearth of lymphocytes in blood and lymph. However, whereas S1P quantities in blood are restored by provision of wild-type bone marrow–derived cells, specifically erythrocytes, S1P in lymph is produced by a nonhematopoietic radioresistant cell type. Injection of wild-type erythrocytes into sphingosine kinase–deficient mice restores S1P in the blood and subsequent egress of S1P1-expressing but not S1P1-deficient lymphocytes from the thymus and spleen. The precise source of lymph S1P remains to be identified. However, these data show that lymphocyte egress is mediated by S1P1 on lymphocytes in response to S1P gradients, which are highest in blood and lymph. CB

Science (15 March 2007) doi:10.1126/science.1139221

Foxp3-flavored ICER-CREM

Regulatory T cells (Treg cells) expressing the transcription factor Foxp3 can suppress immune responses, but how Treg cells accomplish this function remains under investigation. In the European Journal of Immunology, Bodor and colleagues report Foxp3-expressing cells upregulate expression of ICER-CREM, a transcriptional inhibitor, blocking 'downstream' expression of its target gene Il2. ICER-CREM is expressed in Treg cells, but, notably, ICER-CREM expression is induced in newly activated CD4+CD25− T cells after cell-to-cell contact with CD4+Foxp3+ Treg cells. This interaction requires expression of CTLA-4 on the Treg cell and either CD80 or CD86 on the effector T cell. CTLA-4 blockade blunts the ability of Treg cells to inhibit effector T cell expression of interleukin 2 (IL-2). The authors suggest that 'reverse signaling' induced by CTLA-4 through B7 is directly involved in suppressing antigen-activated T cells. How this signaling induces ICER-CREM remains to be elucidated. LAD

Eur. J. Immunol. 37, 884–895 (2007)

Micro-managing T cells

The microRNA miR-181a is involved in B cell and T cell differentiation when it is ectopically expressed in hematopoietic stem cells. In Cell, Davis and Chen and colleagues demonstrate that miR-181a is necessary and sufficient for regulating T cell responsiveness. Retroviral transduction of wild-type but not mutant miR-181a into T cells enhances their responsiveness to agonist peptide, to weakly stimulating partial agonist peptide and even to antagonist peptide that would otherwise negatively regulate wild-type T cell activity. A computational search indicates that mRNA transcripts for several T cell–regulating phosphatases, including Ptpn11 (SHP-2), Ptpn22 and Erk–regulating Dusp5 and Dusp6, could be targets of miR-181a. T cells expressing miR-181a have more Erk phosphorylation, enhanced basal activation, and less protein and mRNA expression of the T cell–regulating phosphatases. 'Knockdown' of endogenous miR-181a reduces T cell responsiveness, Erk activation and thymocyte positive selection while increasing negative selection. Thus, T cell–regulating phosphatases are targets of miR-181a activity. DCB

Cell 129, 1–15 (2007)

T cells target integrin

Semaphorins function in the nervous system as axon guidance factors and in the immune system as regulatory molecules. In Nature, Kikutani and colleagues find that semaphorin 7A (Sema7A) expressed by T cells stimulates integrin α1β1–expressing human monocytes and mouse bone marrow–derived macrophages to produce inflammatory cytokines, including IL-6. Direct interaction between α1β1 and Sema7A leads to peripheral redistribution of focal adhesion kinase, which is pivotal for signaling 'downstream' of integrins via MAP kinases. Sema7A on T cells and α1β1 on macrophages are found at immune contact sites between the two cells. Although antigen-primed and effector T cell generation are not impaired in Sema7A-deficient mice, T cell–dependent inflammation is defective. For example, α1β1-expressing bone marrow–derived macrophages cultured with activated Sema7A-deficient T cells produce much less IL-6, and Sema7A-deficient mice are resistant to contact hypersensitivity and experimental autoimmune encephalitis. Sema7A is thus a critical regulator of cell-mediated inflammation via stimulation of α1β1. DCB

Nature (21 March 2007) doi:10.1038/nature05652

Research notes written by Christine Borowski, Douglas C. Braaten and Laurie A. Dempsey