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B cell antigen receptor isotypes : implications for immune memory

The B cell antigen receptor (BCR) can be expressed in a number of molecular forms during B cell development, and provides context-dependent signals that lead to a variety of cellular outcomes. Isotype switching during an immune response represents a key, irreversible molecular change in BCR structure, where naive BCR isotypes (IgM and IgD) are replaced by switched isotypes (IgG, IgA, IgE) that become markers of antigen experience. Attempts to study isotype-specific BCR signalling in vivo have been hampered, however, by the changes in BCR affinity, location, cell surface phenotype, activation requirements and lifespan that also accompany antigen priming. To address the role of isotype-switched BCR expression during an immune response, homogeneous populations of naive B cells derived from anti-lysozyme immunoglobulin transgenic mice were seeded into a T-dependent immune response to lysozyme in vivo. Comparisons were made between transgenic B cells expressing IgM and IgD BCRs and B cells expressing full length IgG or the unique IgG membrane tail domain. It was found that naive transgenic B cells expressing the IgG membrane tail domain make a more robust response to antigen compared to naive transgenic B cells bearing IgM, both in terms of net clonal expansion and in the production of antibody-forming cells. Transgenic B cells expressing the IgG membrane tail were not activated more efficiently, nor did they have a greater rate of cell division compared to IgM transgenic B cells. Rather, the IgG membrane tail protected B cells from cell death during the process of clonal expansion. This experimental strategy was verified by showing that B cell developmental differences in the bone marrow, as well as phenotypic variations in the marginal zone and follicular B cell subsets of the various transgenic lines did not account for their responses to antigen in vivo. The only apparent determinant of reactivity to antigen in this system was BCR isotype and the expression of the IgG membrane tail domain. This study has identified BCR isotype as a regulator of B cell responses to antigen during an immune response in vivo. It also shows that the IgG membrane tail is the key molecular determinant of the protective effect of IgG expression, leading to increased cell survival during the process of clonal expansion. Isotype switching to IgG may therefore represent a critical component of B cell priming, allowing greater magnitude expansion of memory B cells during a memory response.