Contributions of each of the BAFF receptors to the lymphocyte profiles in C57BL/6 mice

Abstract

BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.Baff^−/− (which harbour no BAFF) and B6.Br3^−/− mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3⁺ and CD4⁺ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.Baff^−/− and B6.Br3^−/− mice; (2) B cells are expanded in B6.Taci^−/− mice, with preferential expansion of follicular (FO) B cells at the expense of CD19⁺CD21^−/loCD23^−/lo B cells but without the preferential expansion of Foxp3⁺ cells observed in B6 mice bearing a Baff transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19⁺CD21^−/loCD23^−/lo B cells are lower in young B6.Bcma^−/− mice, consistent with the inability of B6.Br3^−/−.Taci^−/− mice to recapitulate the B cell profile of B6.Baff^−/− mice; and (4) percentages of Foxp3⁺ cells in B6.Br3^−/−.Taci^−/− mice are intermediate between those in B6.Br3^−/− and B6.Taci^−/− mice despite the B cell profile of B6.Br3^−/−.Taci^−/− mice strongly resembling that of B6.Br3^−/− mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility.