Murine BAFF-receptor residues 168–175 are essential for optimal CD21/35 expression but dispensable for B cell survival

• Published in: Molecular immunology Vol. 47; no. 2-3; pp. 590 - 599
• Main Authors: Mayne, Christopher G., Amanna, Ian J., Hayes, Colleen E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2009
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Amino Acids - immunology; Animals; B cell development; B-Cell Activation Factor Receptor - chemistry; B-Cell Activation Factor Receptor - genetics; B-Cell Activation Factor Receptor - immunology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; BAFF-R; CD21/35; Cell Survival; DNA Mutational Analysis; Female; Gene Expression Regulation; Genetic Vectors - genetics; Male; Mice; Molecular Sequence Data; Mutant Proteins - chemistry; Protein Structure, Tertiary; Receptors, Complement 3b - immunology; Receptors, Complement 3d - immunology; Signal Transduction; Structure-Activity Relationship; Survival signaling; aa; BAFF; TNFR; Bcmd; FO; B cell development; MZ; SLE; TNF; Survival signaling; BAFF-R; MFI; CD21/35; NF
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2009.09.010

BAFF-R (B cell-activating factor belonging to the tumor necrosis factor family receptor) regulates B lymphocyte survival, maturation, homeostasis, and self-tolerance through signaling mechanisms that are not completely understood. A spontaneous BAFF-R mutation, Bcmd-1, disrupts BAFF-R signaling. However, it is not clear why the Bcmd-1-encoded BAFF-R fails to adequately support B cell survival, optimal CD21/35 expression, and B-cell tolerance to dsDNA, since it is 95% identical to the wild-type (wt) BAFF-R and retains the only known signaling motif. A retrotransposon insertion in A/WySnJ strain mice generated the Bcmd-1 allele, replacing the eight C-terminal BAFF-R residues with 21 retrotransposon-encoded residues. New data reported here show that the displaced residues, previously thought to have no signaling role, are essential for optimal CD21/35 expression but contribute little to B cell survival signaling. Analysis of wt Baffr or Bcmd-1 homozygous (A/WySnJ X B6.BCL2)F2 mice confirmed that BCL2 complemented Bcmd-1 for B cell survival but not CD21/35 expression. Through in vivo retroviral transduction experiments, we show that Baffr complemented Bcmd-1 for B cell survival but not CD21/35 expression, whereas the BaffrΔ103–175 deletion mutant lacking the BAFF-R cytoplasmic domain failed to support these functions. Importantly, we show that the BaffrΔ168-175 deletion mutant lacking the retrotransposon-displaced residues, and a BaffrT170A mutant lacking a critical threonine, supported B cell survival but failed to support optimal CD21/35 expression. These data provide the first evidence for a possible bifurcation at the receptor level in the BAFF-R signaling pathway. We suggest that discrete BAFF-R cytoplasmic domains may interact with distinct downstream pathways to provide fine control over B cell survival, maturation, and tolerance induction.