CTLA-4 expression by B-1a B cells is essential for immune tolerance

The importance of CTLA-4 regulation of T cell function is well recognized. Studies here report the expression of this immune-regulator in murine B-1a cells, and demonstrate the critical roles CTLA-4 plays in maintaining self-tolerance through regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. By selectively deleting CTLA-4 from B cells, we show that the conditional knockout mice spontaneously generate T follicular helper (Tfh) cells and germinal centers (GC) in spleen; produce autoantibodies; and, later in life, develop autoimmune pathologies. This impaired immune homeostasis results from B-1a dysfunction when they lose CTLA-4. Thus, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate to antigen-presenting cells and, when reconstituted in normal congenic recipients, induce GC responses and Tfh cells expressing a highly selected repertoire. These findings introduce CTLA-4 regulation of B-1a as a crucial immune-regulatory mechanism. mRNA profile of sorted B-1a cells derived from CTLA-4 B cell conditional knockout (CKO) mice and the control mice