Research articles

Follicular helper T (T_FH) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T_FH cells and limits their numbers in vivo. Ablation of these T_FH-like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses.

Specific variants of the human leukocyte antigens HLA-B27 and HLA-B57 are associated with control of HIV-1 infection, but the mechanisms responsible for this protection are not clear. Here, Elahi et al. show that CD8⁺ cytotoxic T cells restricted by these HLA variants are less susceptible to suppression by and are able to kill regulatory T cells, which may account for their sustained proliferative capacity during chronic HIV-1 infection.

How alum acts as a vaccine adjuvant continues to perplex. Here Marichal et al. now report that alum induces host cell death and release of genomic DNA, which acts as an endogenous damage-associated molecular pattern that stimulates antibody and T cell responses

The widely prescribed beta blocker carvedilol has strong antiarrhythmic effects on the heart, but the underlying mechanisms have been unclear. Qiang Zhou et al. now show that carvedilol, unlike other beta blockers, is also able to block proarrhythmogenic spontaneous calcium waves by directly inhibiting the calcium release channel RyR2. By generating new carvedilol analogs that inhibit RyR2 but not β-adrenergic receptors, the authors provide evidence that antiarrhythmic therapy might be optimized by combining agents that are individually selective for these two targets.

The multiple sclerosis brain shows massive demyelination. Now, Sha Mi and colleagues show that upregulation of DR6 in multiple sclerosis brain is responsible for inhibiting remyelination and brain repair by oligodendrocytes.

Cytotoxic cancer therapy can induce accelerated growth of surviving cancer cells, a phenomenon known as tumor repopulation. This report uncovers a mechanism by which caspase 3 activation in treated cells promotes growth of surviving cells, mediated by iPLA₂ and PGE₂. The level of caspase 3 activation in human tumors also correlates with risk of relapse, suggesting that this pathway may be a determinant of therapeutic effects.

This report identifies Cdk1's phosphorylation of BRCA1 as an important regulator of BRCA1's DNA repair function. Cdk1 inhibition renders cancer cells sensitive to PARP inhibition, and the combination treatment can inhibit tumor growth in vivo, expanding the potential application of PARP inhibitors beyond BRCA1-deficient tumors.

Tenascin C is an extracellular matrix protein previously linked to breast cancer metastasis. Here the authors uncover how tenascin C promotes the fitness of metastasis-initiating cells by sustaining the stem and survival signaling pathways NOTCH and Wnt through specific regulation of Msi1 and Lgr5, respectively.

Understanding the resistance of natural hosts of simian immunodeficiency virus (SIV)—such as sooty mangabeys—to disease progression may yield insights applicable to HIV-1. In this issue, Paiardini et al. report that CD4⁺ central memory T (T_CM) cells from sooty mangabeys do not strongly upregulate CCR5 upon activation and are more resistant to SIV infection than T_CM cells from rhesus macaques, which may contribute to proper immune control and prevention of disease in these natural hosts.

Cancer vaccines are frequently designed to increase the immune response toward one or more of the few known tumor-associated antigens (TAAs). Kottke et al. describe an alternate approach to enhancing anti-tumor immune responses without the need for identification of specific TAAs. They show that systemic delivery of a vesicular stomatis virus–based cDNA library derived from normal tissue induces immune responses that impede growth of tumors of the same tissue type in mice.

Individuals with Chuvash polycythemia have an increased red blood cell count and are prone to developing blood clots. Although mutations affecting the VHL protein are known to be causative, the underlying molecular mechanisms have been unclear. Ryan C Russell et al. now show that VHL targets the key signaling molecule JAK2 for degradation by forming a complex with the SOCS1 protein. The authors also show that JAK2 inhibition has beneficial effects in a mouse model of this disease, pointing to a new therapeutic strategy.

T helper type 17 (T_H17) responses are crucial for immunity to intestinal pathogens. Here, Stephen E. Girardin, Dana J. Philpott and their colleagues report that early production of IL-17A by enteric CD4⁺ T helper cells is important for host defense against Citrobacter and Salmonella infection. Induction of IL-17A is dependent on Nod-like receptors. suggesting early, innate T_H17 responses are involved in controlling enteric pathogens and may have a role in inflammatory bowel disease.

Drugs that block calcium channels reduce pain, but they can cause unwanted side effects. Now, Rajesh Khanna and his colleagues show that a peptide that inhibits the interaction between a calcium channel and a protein called CRMP-2 that activates the channel can reduce pain in animals without the side effects of the channel blocker drugs.

Mutations in the Wnt co-receptor, LRP5, lead to skeletal diseases in humans. Matthew Warman and his colleagues have now developed mutant mice with tissue-specific alterations of Lrp5 expression and found that these mice phenocopy the human skeletal diseases. They also found that Lrp5 acts locally to affect bone homeostasis. Their data suggest that increasing LRP5 signaling in mature bone cells may be a strategy to treat osteoporosis.

Mammalian peptidoglycan recognition proteins (PGRPs) are innate immune effectors that kill bacteria by unclear mechanisms. Kashyap et al. now provide insight into this question and report that PGRPs activate the bacterial two-component system that normally rids the cell of unfolded proteins. PGRP activation of this system abrogates metabolic functions, leading to accumulation of hydroxyl radicals and bacterial cell death.

Ischemia-perfusion injury and high doses of glutamate activate poly(ADP-ribose) (PAR) polymerase-1, leading to PAR polymer synthesis and cell death. Valina Dawson and her colleagues identify Iduna, an endogenous inhibitor of PAR polymer–induced cell death. Iduna is induced with low-dose NMDA receptor activation, binds PAR polymer and protects against cell death both in vitro and in in vivo models of stroke.

Downregulation of estrogen receptor-α (ER-α) in breast tumors can mediate resistance to ER-α–targeted therapies such as tamoxifen. This report sheds light on a therapy resistance–conferring adaptation by identifying a new regulator of ER-α stability. CUE domain–containing protein-2 (CUEDC2) can bind to and promote degradation of ER-α, thereby driving tamoxifen resistance. Elevated CUEDC2 elevation in human breast cancers correlates with attenuated prognosis after tamoxifen treatment, thus suggesting its potential as a clinical predictor.

Gastrointestinal stromal tumors can respond to imatinib mesylate therapy owing to its inhibitory action on tumor cells as well as off-target effects on NK cells. This report shows that a different frequency of genetically determined expression profiles of isoforms of the NK cell receptor NKp30, which show various functional properties, is associated with GIST and influences survival after imatinib treatment.

Dendritic cells produce interleukin-2 (IL-2) and express the IL-2 receptor subunit CD25. Bibiana Bielekova and her colleagues show that dendritic cells, upon interacting with cognate T cells, secrete IL-2 into the immune synapse and use their CD25 to trans-present IL-2 to T cells, facilitating early IL-2 signaling in T cells. Inhibition of CD25 by the monoclonal antibody daclizumab prevents T cell activation and may partly account for the therapeutic effects of daclizumab in patients with multiple sclerosis.

Treatment options for hepatitis C virus (HCV) infection have limited efficacy and high toxicity, resulting in poor adherence and, thus, viral resistance. Identifying previously unrecognized pathways involved in HCV infection may aid the development of new therapeutics. Using an RNAi screen, Lupberger et al. have identified cellular kinases involved in HCV infection of liver cells and have tested the ability of approved inhibitors to block viral entry both in vitro and in vivo.