Volume 12 Issue 5, May 2011

Despite enormous progress in basic research, there are many gaps in understanding human immunity. Here we describe how new investigational tools and computational methods promise to improve the diagnosis, prognosis and therapy of the many diseases with components from the immune system.

B cell generation is disturbed in four newly identified mouse mutants bearing X-linked mutations in the gene encoding the ATPase ATP11C. These findings suggest that the distribution of membrane phospholipids confers a yet-to-be delineated developmental signal.

In addition to their classical function in antigen presentation and their lesser known ability to act as signal transducers, major histocompatibility complex class II molecules are now shown to promote Toll-like receptor signaling. This intriguing role requires intracellular association with the kinase Btk and the costimulatory molecule CD40.

The interaction between hematopoietic stem cells and their niche is critical for the lifelong maintenance of the blood system. New research shows that crosstalk between stromal components of the niche mediates secretion of the chemokine CXCL12.

The inflammasome has been linked to metabolic disorders such as obesity and type 2 diabetes. Data now suggest that the crosstalk between the inflammasome and autophagy critically mediates cytoplasmic receptor NLRP3–dependent activation of the inflammasome by the saturated fatty acids contained in a high-fat diet.

The chemokine CXCL12 is essential for hematopoietic stem cell function. Lapidot and colleagues report that secretion of CXCL12 from bone marrow stromal cells is a cell contact–dependent event, mediated by connexin-43 and connexin-45 gap junctions.

The molecular machinery that regulates the self-renewal of hematopoietic stem cells remains elusive. Flavell and co-workers show that the type E3 ubiquitin ligase Itch negatively regulates the development and function of these cells.

Obesity is characterized by chronic inflammation, but the triggers for this remain unclear. Ting and colleagues demonstrate that a high fat diet activates the inflammasome, resulting in IL-1β release and insulin resistance.

MHC class II is typically involved in the presentation of peptide antigen to CD4⁺ T cells. Cao and colleagues identify a previously unknown intracellular function for MHC class II in promoting Toll-like receptor signaling.

Developing B cells show enhanced sensitivity to negatively selecting signals. Weiss and colleagues show that calcium signals arising from activation of the calcium sensor STIM1 lead to activation of Erk and apoptosis via a protein kinase C-δ and the guanine nucleotide-exchange factor RasGRP1-dependent pathway in transitional self-reactive B cells.

B cells arise via a precise developmental pathway. Goodnow and Beutler report that mice bearing mutations in Atp11c, which encodes a phosphatidylserine 'flippase', have defective B cell generation in the adult bone marrow.

B cells arise via a precise developmental pathway. Goodnow and Beutler report that mice bearing mutations in Atp11c, which encodes a phosphatidylserine 'flippase', have defective B cell generation in the adult bone marrow.

Chronic stimulation of lymphocytes results in upregulation of immunomodulatory IL-10, but the molecular mechanisms of this process have remained unknown. Kubo and colleagues demonstrate that the transcription factor E4BP4 is responsible for this plasticity.