CLTA4-Ig is clinically approved for preventing rejection in kidney transplant recipients but current data suggest that it is less effective for memory T cells, and there is limited information on its effect on effector T cells. We previously reported that treatment with CTLA4-Ig was able to rescue BALB/c (B/c) heart allografts in C57BL/6 (B/6) recipients from rejection, even when treatment was started on post-operative day (POD) 6 – just 2 days prior to complete cessation of heartbeat and when there already was substantial T cell expansion and infiltration into the allograft. Furthermore, delayed CLTA4-Ig had similar effects in B cell-deficient recipients, suggesting that the ability of CTLA4-Ig to stop ongoing acute rejection was not dependent on its ability to inhibit B cell activation and alloantibody production. Here we investigated the effects of delayed CTLA4-Ig on T cell effector function in mice undergoing allograft rejection. We observed that treating recipients with CTLA4-Ig on POD 6 did not reduce the number of graft-infiltrating CD4⁺ or CD8⁺ T cells (GICs) examined 8d later. We tested the ability of CTLA4-Ig to inhibit IFNg production in vivo, where brefeldin A was injected into recipients to prevent the secretion of IFNg at 32h after CTLA4-Ig treatment and the GICs were harvested 15h later. CTLA4-Ig was able to reduce the frequency of GICs producing IFNg by 50% compared to untreated acutely rejecting controls. We also tested the ability of CTLA4-Ig to inhibit CD8-mediated cytolysis in vivo. B/6 mice were immunized with OVA⁺ B/6-B/c F1 splenocytes to generate OVA-specific CTLs, received CTLA4-Ig on day 6 post-immunization, and SIINFEKL/CFSE^lo– or control peptide/CFSE^hi -pulsed B/6 spleen cell targets 24h later. The target cells were enumerated 3 hours later, and we observed that CTLA4-Ig was able to induce a modest (~25%) but statistically significantly reduction in specific CTL activity. This more modest effect by CTLA4-Ig is consistent with lower signaling requirements for cytolysis compared to cytokine production. Taken together, these results demonstrate the unexpected ability of CTLA4-Ig to inhibit T cell effector responses, underscoring the importance of the CD28-B7 co-stimulation pathway for IFNg production, and to a lesser extent, for CTL activity. Thus CTLA4-Ig may prove to be a valuable adjunct therapy for patients undergoing acute rejection.

CITATION INFORMATION: Young J, Khiew S, Yang J, Alegre M.-L, Chong A. CTLA4-Ig Inhibits Effector CD8⁺ T Cell Function In Vivo and Rescues Ongoing Acute Allograft Rejection. Am J Transplant. 2017;17 (suppl 3).

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