CD21 Triggers Autoimmune B Cell Activation in Lupus via TLR7 Pathway

Systemic lupus erythematosus (SLE) is driven partly by extrafollicular (EF) B cells that rapidly differentiate into autoantibody-secreting cells (ASCs) without passing through germinal centers. CD21-low (CD21lo) B cells — analogous to human DN2 cells implicated in SLE — are key contributors to this pathway, yet the molecular signals governing their emergence were poorly understood. This study dissects those mechanisms with exceptional temporal resolution.

The researchers developed an adoptive transfer system by introducing naïve wild-type or TLR7-knockout (Tlr7-KO) B cells with natural BCR repertoires into 564Igi transgenic mice. These hosts provide a TLR7-rich autoimmune environment enriched with nuclear autoantigens and T cell help, amplifying autoreactive responses while preserving donor BCR diversity. Donor cells were tracked over 7 days using congenic markers and CellTrace Violet proliferation dye.

Key results showed that WT donor B cells began expanding by day 4, rapidly co-opting ~60% of the host plasma cell compartment by day 6 — an entirely EF process confirmed by BCL6-deficient B cell transfers. In contrast, Tlr7-KO donor cells failed to proliferate, produced virtually no ASCs (24-fold reduction), and showed impaired DN2-like CD21lo cell generation (9.7-fold reduction). CD21 downregulation was tightly coupled to proliferative history: undivided cells retained CD21 expression, while terminally divided cells (7+ divisions) were predominantly CD21lo and ASC-fated. Crucially, continuous engagement of CD21 with complement fragments C3d and iC3b triggered receptor downregulation before proliferation began, implicating complement-CD21 signaling as an upstream initiator.

BCR repertoire analysis tracked clonal evolution from naïve follicular B cells through EF differentiation. Protoautoreactive clones were selectively expanded, with somatic mutations driving increased self-reactivity over time. This demonstrated that even polyclonal naïve B cells carry subsets primed for autoreactive evolution under permissive autoimmune conditions.

The study establishes a mechanistic model in which complement-opsonized autoantigens engage CD21, triggering its downregulation and licensing TLR7-dependent proliferative and differentiation programs that culminate in EF ASC output. CD21 thus acts paradoxically: initially as a co-receptor lowering the activation threshold, then as a gate whose loss marks commitment to the autoimmune EF fate. These findings nominate CD21 and its complement ligand interactions as tractable therapeutic targets for intercepting autoreactive B cell responses early in SLE pathogenesis.