Davina Dadley-Moore

RESEARCH HIGHLIGHTS

of monoclonal antibodies specific early phase response when trans- for type II collagen together with ferred to mice that are deficient in lipopolysaccharide and is character- both T-bet and RAG2. Consistent IN BRIEF ized by an early innate phase followed with this role for DCs in the early by a later adaptive phase. Compared inflammatory phase, the authors with wild-type mice, the onset of showed that T-bet-deficient DCs pro- T-CELL DEVELOPMENT CAIA in T-bet-deficient mice was duced less of the pro-inflammatory Premature expression of chemokine receptor CCR9 delayed and was less severe in both mediators interleukin-1α and impairs T cell development. the initial and the late phases. CC-chemokine ligand 3 (CCL3) Uehara, S. et al. J. Immunol. 176, 75–84 (2006) Mice that are deficient in RAG2 and more CCL17, a ligand for the Only late CD4–CD8– double-negative (DN) thymocytes and + + (recombination-activating gene 2), TH2-cell-specific chemokine CD4 CD8 double-positive thymocytes express CC-chemokine which completely lack B and T cells, receptor CCR4, than wild-type DCs. receptor 9 (CCR9). To investigate whether expression of CCR9 developed early joint inflammation, Moreover, the ability of DCs to prime controls the migration of thymocytes and their retention in the but the later phase was attenuated. naive T cells in vivo was impaired thymus, Uehara et al. generated transgenic mice in which CCR9 + + And mice that are deficient in both in the absence of T-bet. was expressed throughout T-cell development. CD4 and CD8 single-positive (SP) thymocytes could exit the thymus, indicating T-bet and RAG2 were resistant to the In light of these results, that CCR9 downregulation is not essential for SP thymocyte induction of arthritis. T-bet could be a target to control emigration. By contrast, ectopic expression of CCR9 by early To further assess the cellular inflammation at multiple points in DN thymocytes partially blocked thymocyte development at the components of the innate phase, both innate and adaptive immune DN3 stage, and CD25+ thymocytes (DN2 and DN3 thymocytes) the authors carried out adoptive- responses. were found throughout the cortex rather than at the subcapsular transfer experiments. Transfer of Lucy Bird region. These results indicate that the timing of CCR9 expression is important for normal thymocyte development and that this wild-type DCs to T-bet-deficient ORIGINAL RESEARCH PAPER Wang, J. et al. might be because CCR9 controls CD25+ thymocyte localization. mice on day 1 of CAIA induction Transcription factor T-bet regulates inflammatory restored inflammatory arthritis, arthritis through its function in dendritic cells. J. Clin. Invest. 12 Jan 2006 (doi:10.1172/JCI26631) HAEMATOPOIESIS and wild-type DCs restored the Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Trowbridge, J. J. et al. Nature Med. 12, 89–98 (2006) The study by Núñez and colleagues Glycogen synthase kinase 3 (GSK3) regulates several signalling provides evidence (supported in part pathways (such as the Notch and WNT signalling pathways) by the other two studies) that TLRs that affect the in vitro function of haematopoietic stem cells and NALP3 induce immune responses (HSCs). In this study, non-obese diabetic–severe combined through recognition of the same or immunodeficient mice were transplanted with HSCs from normal similar microbial structures and that mice in the presence or absence of an ATP-competitive inhibitor IL-1β secretion is independently of GSK3. Treatment with the GSK3 inhibitor increased recipient regulated at two stages: the first is haematopoietic-cell reconstitution in both the short and the long TLR dependent and results in nuclear- term and thereby increased recipient survival. Further analysis showed that the GSK3 inhibitor increased the production of factor-κB-mediated transcription of the β progenitor cells while maintaining the number of HSCs, leading gene that encodes pro-IL-1 , and the the authors to suggest that treatment with GSK3 inhibitors are also structurally similar to purine second is NALP3 dependent and results might be a useful therapeutic approach to increase recipient bases and have recently been reported in cleavage of pro-IL-1β into IL-1β. haematopoietic-cell reconstitution after HSC transplantation. to be a danger signal) and calcium Taken together, these results show pyrophosphate dihydrate (both of which that NALP3 has a crucial role in host HAEMATOPOIESIS elicit inflammatory responses; known defence against certain bacteria as gout and pseudogout, respectively) and that it might be a proximal Antagonistic effect of CCAAT enhancer-binding induce caspase-1-dependent IL-1β sensor of cellular stress and danger protein-α and Pax5 in myeloid or lymphoid lineage secretion by primed macrophages, signals. In addition, these studies choice in common lymphoid progenitors. and this relies on components of the provide insight into the mechanisms Hsu, C.-L. et al. Proc. Natl Acad. Sci. USA 103, 672–677 (2006) inflammasome, including NALP3. Dixit of autoinflammatory disorders that Although lymphoid-lineage-committed progenitors, such and colleagues found that NALP3 is also involve NALP3. as common lymphoid progenitors (CLPs) and pro-T cells, are required for pro-caspase-1 activation Davina Dadley-Moore mainly destined to become lymphocytes, they maintain a latent by another danger signal, ATP (which, myeloid differentiation potential, which can be initiated by in vivo, is released into the extracellular ORIGINAL RESEARCH PAPERS stimulation through ectopic interleukin-2 receptor (IL-2R). This environment by dying cells), and Kanneganti, T.-D. et al. Bacterial RNA and study shows that IL-2R triggering of CLPs and pro-T cells results small antiviral compounds activate caspase-1 after exposure to certain Gram- in rapid upregulation of the myeloid-related transcription through cryopyrin/Nalp3. Nature 11 Jan 2006 factor CCAAT enhancer-binding protein-α (C/EBPα). Moreover, positive bacteria but not certain (doi:10.1038/nature04517) | Martinon, F., ectopic expression of C/EBPα in these cells leads to myeloid- Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gram-negative bacteria. cell development. C/EBPα expression completely suppressed It is thought that, similar to recognition Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 11 Jan 2006 expression of the B-cell-lineage transcription factor PAX5 in by TLRs, pathogen-associated molecular (doi:10.1038/nature04516) | Mariathasan, S. CLPs and pro-T cells. By contrast, IL-2R stimulation of pro- patterns interact with the leucine- et al. Cryopyrin activates the inflammasome in B cells did not lead to lineage conversion, owing to insufficient rich-repeat domains of NALPs, leading response to toxins and ATP. Nature 11 Jan 2006 downregulation of PAX5 expression by C/EBPα, indicating that (doi:10.1038/nature04515) to activation of the inflammasome. complete loss of PAX5 is crucial for lymphoid-to-myeloid-lineage conversion.