Cutting edge: CTLA-4Ig inhibits memory B cell responses and promotes allograft survival in sensitized recipients

Sensitized recipients with pretransplant donor-specific Abs are at higher risk for Ab-mediated rejection than nonsensitized recipients, yet little is known about the properties of memory B cells that are central to the recall alloantibody responses. Using cell enrichment and MHC class I tetramers, C57BL/6 mice sensitized with BALB/c splenocytes were shown to harbor H-2K^d-specific IgG⁺ memory B cells with a post-germinal center phenotype (CD73⁺CD273⁺CD38^hiCD138^-GL7^-). These memory B cells adoptively transferred into naive mice without memory T cells recapitulated class-switched recall alloantibody responses. During recall, memory H-2K^d-specific B cells preferentially differentiated into Ab-secreting cells, whereas in the primary response, H-2K^d-specific B cells differentiated into germinal center cells. Finally, our studies revealed that, despite fundamental differences in alloreactive B cell fates in sensitized versus naive recipients, CTLA-4Ig was unexpectedly effective at constraining B cell responses and heart allograft rejection in sensitized recipients.