Hot off the presses! Mar 01

The Mar 01 issue of the is now up on Pubget (About ): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Educating the public
  - Nature Immunology 11(3):181 (2010)
  California has one of the most prestigious public university systems. However, budget woes and lack of clear strategic planning may undermine its continued success.
• In vivo veritas: the surprising roles of Fc receptors in immunity
  - Nature Immunology 11(3):183-185 (2010)
  Jeffrey Ravetch describes how he came to identify the in vivo function of the once mysterious Fc receptors.
• Vanilloid flavor for a good appetite?
  - Nature Immunology 11(3):187-189 (2010)
  Members of the transient receptor potential vanilloid ion-channel family are expressed in a wide variety of cells and function as sensors of mechanical stress. The second such family member, TVRP2, is now also linked to phagocytosis in macrophages.
• CD8+ thymocyte differentiation: T cell two-step
  - Nature Immunology 11(3):189-190 (2010)
  A new study demonstrates that commitment to the CD8 lineage in the thymus requires sequential T cell antigen receptor (TCR) and interleukin 7 (IL-7) signaling. The TCR signal first induces IL-7 responsiveness, then recognition of IL-7 induces the nuclear factor Runx3, which specifies the CD8 lineage.
• Voltage control for B cell activation
  - Nature Immunology 11(3):191-192 (2010)
  Transient formation of reactive oxygen species (ROS) accompanies B cell signaling and activation. Now the voltage-gated proton channel HVCN1 has been linked to ROS formation and B cell activation.
• Controlling stem cell fate one substrate at a time
  - Nature Immunology 11(3):193-194 (2010)
  Hematopoietic stem cell self-renewal is tightly regulated. Regulation of the stability of c-Myc protein contributes to this control of hematopoietic stem cell quiescence and repopulation.
• Research Highlights
  - Nature Immunology 11(3):195 (2010)
  
• Raising the NKT cell family
  Godfrey DI Stankovic S Baxter AG - Nature Immunology 11(3):197-206 (2010)
  Natural killer T cells (NKT cells) are CD1d-restricted, lipid antigen–reactive, immunoregulatory T lymphocytes that can promote cell-mediated immunity to tumors and infectious organisms, including bacteria and viruses, yet paradoxically they can also suppress the cell-mediated immunity associated with autoimmune disease and allograft rejection. Furthermore, in some diseases, such as atherosclerosis and allergy, NKT cell activity can be deleterious to the host. Although the precise means by which these cells carry out such contrasting functions is unclear, recent studies have highlighted the existence of many functionally distinct NKT cell subsets. Because their frequency and number vary widely between individuals, it is important to understand the mechanisms that regulate the development and maintenance of NKT cells and subsets thereof, which is the subject of this review.
• Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase–substrate complex
  - Nature Immunology 11(3):207-215 (2010)
  Hematopoietic stem cell (HSC) differentiation is regulated by cell-intrinsic and cell-extrinsic cues. In addition to transcriptional regulation, post-translational regulation may also control HSC differentiation. To test this hypothesis, we visualized the ubiquitin-regulated protein stability of a single transcription factor, c-Myc. The stability of c-Myc protein was indicative of HSC quiescence, and c-Myc protein abundance was controlled by the ubiquitin ligase Fbw7. Fine changes in the stability of c-Myc protein regulated the HSC gene-expression signature. Using whole-genome genomic approaches, we identified specific regulators of HSC function directly controlled by c-Myc binding; however, adult HSCs and embryonic stem cells sensed and interpreted c-Myc-regulated gene expression in distinct ways. Our studies show that a ubiquitin ligase–substrate pair can orchestrate the molecular program of HSC differentiation.
• Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cell responses to influenza
  - Nature Immunology 11(3):216-224 (2010)
  The question of which dendritic cells (DCs) respond to pulmonary antigens and cross-prime CD8+ T cells remains controversial. We show here that influenza-specific CD8+ T cell priming was controlled by different DCs at different times after infection. Whereas early priming was controlled by both CD103+CD11blo and CD103−CD11bhi DCs, CD103−CD11bhi DCs dominated antigen presentation at the peak of infection. Moreover, CD103−CD11bhi DCs captured exogenous antigens in the lungs and directly cross-primed CD8+ T cells in the draining lymph nodes without transferring antigen to CD8α+ DCs. Finally, we show that CD103−CD11bhi DCs were the only DCs to express CD70 after influenza infection and that CD70 expression on CD103−CD11bhi DCs licensed them to expand CD8+ T cell populations responding to both influenza and exogenous ovalbumin.
• Chromogranin A is an autoantigen in type 1 diabetes
  Stadinski BD Delong T Reisdorph N Reisdorph R Powell RL Armstrong M Piganelli JD Barbour G Bradley B Crawford F Marrack P Mahata SK Kappler JW Haskins K - Nature Immunology 11(3):225-231 (2010)
  Autoreactive CD4+ T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4+ T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-Ag7 in an atypical manner, occupying only the carboxy-terminal half of the I-Ag7 peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.
• TRPV2 has a pivotal role in macrophage particle binding and phagocytosis
  - Nature Immunology 11(3):232-239 (2010)
  Macrophage phagocytosis is critical for defense against pathogens. Whereas many steps of phagocytosis involve ionic flux, the underlying ion channels remain ill defined. Here we show that zymosan-, immunoglobulin G (IgG)- and complement-mediated particle binding and phagocytosis were impaired in macrophages lacking the cation channel TRPV2. TRPV2 was recruited to the nascent phagosome and depolarized the plasma membrane. Depolarization increased the synthesis of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), which triggered the partial actin depolymerization necessary for occupancy-elicited phagocytic receptor clustering. TRPV2-deficient macrophages were also defective in chemoattractant-elicited motility. Consequently, TRPV2-deficient mice showed accelerated mortality and greater organ bacterial load when challenged with Listeria monocytogenes. Our data demonstrate the participation of TRPV2 in early phagocytosis and its fundamental importance in innate immuni! ty.
• An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells
  D'Cruz LM Knell J Fujimoto JK Goldrath AW - Nature Immunology 11(3):240-249 (2010)
  E proteins are basic helix-loop-helix transcription factors that regulate many key aspects of lymphocyte development. Thymocytes express multiple E proteins that are thought to provide cooperative and compensatory functions crucial for T cell differentiation. Contrary to that, we report here that the E protein HEB was uniquely required at the CD4+CD8+ double-positive (DP) stage of T cell development. Thymocytes lacking HEB showed impaired survival, failed to make rearrangements of variable-α (Vα) segments to distal joining-α (Jα) segments in the gene encoding the T cell antigen receptor α-chain (Tcra) and had a profound, intrinsic block in the development of invariant natural killer T cells (iNKT cells) at their earliest progenitor stage. Thus, our results show that HEB is a specific and essential factor in T cell development and in the generation of the iNKT cell lineage, defining a unique role for HEB in the regulation of lymphocyte maturation.
• Regulation of IL-9 expression by IL-25 signaling
  Angkasekwinai P Chang SH Thapa M Watarai H Dong C - Nature Immunology 11(3):250-256 (2010)
  The physiological regulation of the expression of interleukin (IL)-9, a cytokine traditionally regarded as being TH2 associated, remains unclear. Here, we show that IL-9-expressing T cells generated in vitro in the presence of transforming growth factor-β and IL-4 express high levels of mRNA for IL-17 receptor B (IL-17RB), the receptor for IL-25. Treatment of these cells with IL-25 enhances IL-9 expression in vitro. Moreover, transgenic and retroviral overexpression of IL-17RB in T cells results in IL-25-induced IL-9 production that is IL-4 independent. In vivo, the IL-25–IL-17RB pathway regulates IL-9 expression in allergic airway inflammation. Thus, IL-25 is a newly identified regulator of IL-9 expression.
• Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells
  - Nature Immunology 11(3):257-264 (2010)
  Immature CD4+CD8+ (double-positive (DP)) thymocytes are signaled via T cell antigen receptors (TCRs) to undergo positive selection and become responsive to intrathymic cytokines such as interleukin 7 (IL-7). We report here that cytokine signaling is required for positively selected thymocytes to express the transcription factor Runx3, specify CD8 lineage choice and differentiate into cytotoxic-lineage T cells. In DP thymocytes genetically engineered to be cytokine responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into mature CD8+ T cells, completely circumventing positive selection. We conclude that TCR-mediated positive selection converts DP cells into cytokine-responsive thymocytes, but it is subsequent signaling by intrathymic cytokines that specifies CD8 lineage choice and promotes differentiation into cytotoxic-lineage T cells.
• HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species
  Capasso M Bhamrah MK Henley T Boyd RS Langlais C Cain K Dinsdale D Pulford K Khan M Musset B Cherny VV Morgan D Gascoyne RD Vigorito E Decoursey TE Maclennan IC Dyer MJ - Nature Immunology 11(3):265-272 (2010)
  Voltage-gated proton currents regulate generation of reactive oxygen species (ROS) in phagocytic cells. In B cells, stimulation of the B cell antigen receptor (BCR) results in the production of ROS that participate in B cell activation, but the involvement of proton channels is unknown. We report here that the voltage-gated proton channel HVCN1 associated with the BCR complex and was internalized together with the BCR after activation. BCR-induced generation of ROS was lower in HVCN1-deficient B cells, which resulted in attenuated BCR signaling via impaired BCR-dependent oxidation of the tyrosine phosphatase SHP-1. This resulted in less activation of the kinases Syk and Akt, impaired mitochondrial respiration and glycolysis and diminished antibody responses in vivo. Our findings identify unanticipated functions for proton channels in B cells and demonstrate the importance of ROS in BCR signaling and downstream metabolism.