Nature Immunology pp 849 - 856

In the September issue of Nature Immunology, scientists from Tokyo and Basel report how young B cells can provide their own signals to allow their maturation into antibody-producing cells. The new data elucidate a long-standing conundrum concerning how these cells recognize that they have successfully executed an essential early step. Thus, scientists need search no more for that elusive external signal, as it is not necessary for this 'quality control' step.

B cells develop in the bone marrow, where antibody assembly from its 'light' and 'heavy' chain components must follow a strict sequence of steps. First, the gene encoding the heavy chain is cut and pasted together ('rearranged') from sequences scattered about the chromosome. This is followed by the rearrangement of light chains—but if and only if the heavy chain protein is made. Thus, the young B cells have established a checkpoint to stop and assess whether they have made a good heavy chain protein. The researchers show how charged amino acids in a companion protein called lambda 5, which pairs with properly made new heavy chains, stimulate clustering of these molecules and initiate the signal to advance to the next stage. Mutation of these essential charged residues blocks further B cell development. Thus, lambda 5 acts as a 'quality control officer' during antibody gene rearrangement.

Nature Immunology pp 843 - 848

Patients with defects in the enzyme AID (activation-induced cytosine deaminase) are prone to recurrent microbial infections because of their inability to make effective antibodies. In the September issue of Nature Immunology, Japanese and French researchers identified multiple mutations in the AID gene (AICDA) from patients diagnosed with hyper-IgM syndrome type 2 (HIGM2). AID initiates genetic alterations within antibody genes that give rise to high-affinity serum antibodies (called somatic hypermutation, or SHM), and directs the production of different classes of antibodies by the process known as class-switch recombination (CSR). This latter process is required to make the IgG molecules found in blood or the IgA found in tears, saliva and intestinal secretions.

The AID mutants reported in the new study failed to direct antibody maturation, but not all mutants were defective for the same reason—some mutants were defective for CSR but not for SHM, whereas other lost both activities but retained their core cytosine deaminase function. These results show that AID requires specific cofactors to help it, and that discrete protein domains are required for these interactions. This work paves the way to now look for these accessory proteins.

Nature Immunology pp 920 - 927

Uncontrolled inflammation is a chief cause of morbidity and mortality. In the September issue of Nature Immunology, scientists show that a natural molecule in our body known as SIGIRR regulates inflammation by dampening signals that initiate inflammatory responses. This finding helps us to understand how our body keeps inflammation in check and opens new avenues for designing anti-inflammatory treatments.

Our body senses bacteria and viruses with a set of molecules known as Toll-like receptors (TLRs). TLRs belong to a bigger family of molecules that include the interleukin 1 receptor, which is commonly associated with inflammation. Li and colleagues show that SIGIRR, which is a member of this family of molecules, suppresses rather than initiates inflammation. Understanding how SIGIRR is switched on should provide targets for stopping unwanted inflammation.

Nature Immunology pp 874 - 881

A long-standing puzzle has been how calcium can selectively control multiple conflicting signaling pathways in T cells. In the September issue of Nature Immunology, scientists report that part of the answer lies with a protein called calcipressin 1 (Csp1).

Calcineurin, a calcium-dependent phosphatase, mediates a wide variety of signaling pathways in the immune, nervous and cardiovascular systems. T cell expansion is calcineurin dependent but, confusingly, so is T cell death. Frank McKeon and colleagues attacked this dilemma by generating mice that lack Csp1, a known regulator of calcineurin. They found that Csp1 functions to ensure that genes that require strong activation signals, such as Fas ligand, remain silent during T cell clonal expansion. However, genes such as the one encoding IFN-gamma that can be triggered with little provocation and are required for expansion are permitted to be expressed. Thus, Csp1 is important because it modulates the pattern of calcineurin-dependent gene expression.

Nature Immunology pp 866 - 873

Hematopoietic stem cells (HSCs) provide a source of T cell precursors, but the identity of the T cell progenitors capable of migrating from the bone marrow, the source of all adult blood components, to the thymus, where T cells develop, has remained elusive. In the September issue of Nature Immunology, scientists have identified a population of progenitor cells that can colonize the thymus and produce T cells.

Von Boehmer and colleagues defined a new population of T cell progenitor cells, called common lymphoid precursor 2 or CLP-2, which could produce both B and T cells in culture. Injection of these cells into the bloodstream of mice showed that CLP-2 cells could home to the thymus and give rise to T cells in thymic organ cultures. This indicates that the CLP-2 subset is the missing link between HSCs and intrathymic T cell precursors. However, the data do not exclude the possibility that other, as-yet-unidentified precursor populations may also have this ability.