Selective CD28 blockade results in superior inhibition of donor-specific T follicular helper cell and antibody responses relative to CTLA-4-Ig

• Published in: American journal of transplantation Vol. 18; no. 1; pp. 89 - 101
• Main Authors: Badell, IR, La Muraglia, GM, Liu, D, Wagener, ME, Ding, G, Ford, ML
• Format: Journal Article
• Language: English
• Published: 14-08-2017
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.14400

Donor-specific antibodies (DSA) are a barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade with CTLA-4-Ig has shown promise as a potential therapeutic strategy to control DSA. T follicular helper (Tfh) cells, a subset of CD4
+
T cells required for optimum antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8
+
T cells relative to CTLA-4-Ig, but the impact of CD28-specific blockade on CD4
+
Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model, and then utilized this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5
+
PD-1
hi
Tfh and CD95
+
GL7
+
germinal center B cells, and DSA formation as compared to CTLA-4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA-4 expression, suggesting an important role for CTLA-4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.