Controlling adolescent B cells

Less than 10% of the immature B cells that exit the bone marrow will complete their development in the spleen to become mature follicular or marginal-zone B cells. However, little is known about the molecular mechanisms that govern this final rite of passage. Now, a report in The Journal of Immunology indicates that Id2 has an important role.

Transcription factors that contain a basic helix–loop–helix (bHLH) motif have been shown to be crucial for various cell-differentiation processes. The transcriptional activity of the bHLH proteins can be regulated by members of the Id family, another class of HLH proteins. Id proteins lack a DNA-binding region. Instead, they function solely by dimerization with the bHLH family, and they inhibit the functions of this family in a dominant-negative manner.

To examine the role of Id proteins in B-cell development in the spleen, Becker-Herman, Lantner and Shachar first measured the level of expression of Id proteins in immature and mature splenic B cells. Similar levels of Id1 and Id3 messenger RNA were detected in immature and mature B-cell populations; however, the expression of Id2 was markedly reduced in mature B cells.

The authors hypothesized that Id2 might limit B-cell maturation in the spleen. In support of this, Id2-deficient mice were shown to have an increased number of mature splenic B cells. Further analysis indicated that the accumulation of mature B cells in Id2^−/− mice was not owing to increased cellular life span or aberrant B-cell development in the bone marrow. Strikingly, although there is a greater number of mature B cells in Id2^−/− mice, marginal-zone (IgM⁺IgD⁻CD21^hi) B cells are virtually absent.

A potential target of Id2 is the bHLH protein E2A, which is required for the initiation of B-cell development. Immature and mature B cells express equivalent levels of E2A mRNA. E2A-specific E2-box-binding activity, however, was shown to be markedly reduced in immature B cells. Immunoprecipitation studies showed directly that Id2 and E2A form heterodimers in immature B cells, which indicates that Id2 might be responsible for the inhibition of E2A function.

This study shows, for the first time, a role for Id2 in the regulation of B-cell maturation in the spleen. In this process, it seems that Id2 has two functions — it allows commitment to the marginal-zone B-cell lineage and controls the differentiation of follicular B cells. But, the genes that are regulated by Id2 at this stage of development have not been identified yet.