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Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-beta, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'T(H)-9' cells directly. Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.

Most mucosal surfaces of the mammalian body are colonized by microbial communities (“microbiota”). A high density of commensal microbiota inhabits the intestine and shields from infection (“colonization resistance”). The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10−/−, VILLIN-HACL4-CD8) with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen.

Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE −CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

Pannexin hemichannel–mediated release of ATP provides an autocrine, costimulatory signal for T cell activation.

Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.

IntroductionImmunity to infections depends on the successful integration of innate and adaptive defense strategies. 1 Cells of the innate immune system, such as macrophages and dendritic cells, recognize pathogen-associated molecular patterns shared by many microbes but not found in higher eukaryotes, via members of the Toll-like receptor (TLR) family. 2,3 TLR-dependent signaling pathways can directly induce macrophage antimicrobial programs but also initiate inflammatory cell recruitment and help prime cells of the adaptive immune system to amplify bactericidal effector mechanisms. Experimental infections with microorganisms have been used successfully to uncover the intricacies governing the interplay between innate and adaptive immunity. 4,5 For example, cell-wall components of Mycobacterium tuberculosis, the causative organism of tuberculosis, critically depend on TLR2 and TLR4 to induce secretion of the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣) and interleukin (IL-12, necessary for differentiating T-helper 1 cells). 6 Subsequently, mycobacteria-primed T cells secrete interferon gamma (IFN-␥) as a critical macrophageactivating agent. Eradication of mycobacteria is achieved only when both arms of the immune system are fine-tuned for full antimicrobial potency.Functionally, the Toll-mediated induction of antimicrobial effector systems is highly conserved between Drosophila melanogaster (D melanogaster) and Homo sapiens. 7,8 Another example for human evolutionarily ancient effector mechanisms is granulysin (a granule-stored bactericidal molecule), which is homologous to the amoebapores of Entamoeba histolytica. 9,10 Thus, there is ample precedence for evolutionarily conserved signatures governing individual facets of the immune response. To uncover novel regulatory pathways in innate responses to infection, we performed a microarray-based gene-expression screen with human macrophages infected with mycobacteria or conserved bacterial structures. We found mRNA for WNT5A, a homolog of Wingless in Drosophila species, to be consistently up-regulated in response to all stimuli.Wingless was originally characterized as a segment polarity gene in D melanogaster, which is essential in embryonic segmentation and patterning (reviewed in Klingensmith and Nusse 11 ). Various homologs of the Wingless protein, termed WNT, are involved in embryonic development of nonvertebrates and vertebrates, 12,13 where WNT signaling determines cell motility, differentiation, and apoptosis. 14 In mammalian hematopoiesis, WNT signaling is essential for stem-cell homeostasis 15 and lymphocyte differentiation. 16,17 Most recently, one member of the WNT family of proteins, WntD, was shown to be involved in regulating antibacterial defenses in Drosophila. 18 To date, however, WNT Center Borstel, Germany), phorbol-12-myristate13-acetate (PMA), calcium ionophore A23187 (both Sigma Aldrich, Taufkirchen, Germany), and phytohemagglutinin (PHA) were used for stimulation. To rule out the presence of lipopolysaccharides (LPSs) in the...

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