Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific

Abstract

Anti-donor antibodies cause immunologic injury in transplantation. CD28 blockade with CTLA-4-Ig has the ability to reduce the incidence of these donor-specific antibodies (DSA), but its mechanism is suboptimal for the inhibition of alloimmunity in that CTLA-4-Ig blocks both CD28 costimulation and CTLA-4 coinhibition. Thus selective CD28 blockade that spares CTLA-4 has potential to result in improved inhibition of humoral alloimmunity. To test this possibility, we utilized a full allogeneic mismatch murine transplant model and T follicular helper (Tfh):B cell co-culture system. We observed that selective blockade with an anti-CD28 domain antibody (dAb) compared to CTLA-4-Ig led to superior inhibition of Tfh cell, germinal center, and DSA responses in vivo and better control of B cell responses in vitro. CTLA-4 blockade enhanced the humoral alloresponse and, in combination with anti-CD28 dAb, abrogated the effects of selective blockade. This CTLA-4-dependent inhibition was Tfh cell specific in that CTLA-4 expression by Tfh cells was necessary and sufficient for the improved humoral inhibition observed with selective CD28 blockade. As CD28 blockade attracts interest for control of alloantibodies in the clinic, these data support selective CD28 blockade as a superior strategy to address DSA via the sparing of CTLA-4 and more potent targeting of Tfh cells.