B-cell development

Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. Tze, L. E. et al. PLoS Biol. 3, e82 (2005).

This study shows that basal signalling through the B-cell receptor (BCR) of immature B cells is crucial to suppress expression of the recombination-activating genes (RAG1 and RAG2) and to prevent 'back-differentiation' to the pro-B-cell stage. Therefore, such basal signalling is important to maintain allelic exclusion of the immunoglobulin light chains (which rearrange at this stage of development) and ensure self-tolerance. When basal IgM signalling in immature B cells was inhibited, microarray analysis and flow cytometry showed the upregulation of genes and proteins that are selectively expressed by pro-B cells. The requirement for basal signalling to maintain B-cell development could be an important quality-control mechanism to test for a functional BCR.

Antibody responses

MutSα binds to and promotes synapsis of transcriptionally activated immunoglobulin switch regions. Larson, E. D. et al. Curr. Biol. 15, 470–474 (2005).

Class-switch recombination (CSR) — the process by which a new immunoglobulin constant region is joined to the rearranged heavy-chain variable (VDJ) region — requires activation-induced cytidine deaminase (AID) and the mismatch-repair heterodimer MutSα (MSH2–MSH6). This study clarifies the role of MutSα by showing that it specifically binds to regions of G4 DNA (four DNA strands associated through bonds between guanines) in transcribed switch regions that are produced during CSR and to the U·G mismatches that are created by AID. Binding of MutSα promoted interactions between the G-rich loops, thereby leading to switch-region synapsis.

Natural killer cells

A subset of natural killer cells achieve self-tolerance without expressing inhibitory receptors specific for self MHC molecules. Fernandez, N. C. et al. Blood 22 Feb 2005 (10.1182/blood-2004-08-3156).

Natural killer (NK) cells are thought to express at least one inhibitory receptor specific for a self-MHC class I molecule, and this is thought to maintain NK-cell self-tolerance. However, Fernandez et al. detected a population of NK cells that lack expression of all known inhibitory receptors specific for self-MHC class I molecules. These NK cells were hyporesponsive in vitro when cultured with either cells lacking cell-surface expression of MHC class I molecules or tumour cells expressing ligands for NK-cell activating receptors. Similar hyporesponsiveness was observed in vivo, as these NK cells were inefficient at mediating rejection of bone marrow lacking cell-surface expression of MHC class I molecules, indicating that, for some NK cells, self-tolerance is not a result of inhibitory-receptor interaction with self-MHC class I molecules but of hyporesponsiveness to self.