Belatacept-Resistant Rejection Is Associated With CD28⁺ Memory CD8 T Cells

Area of Science:

• Immunology
• Transplantation immunology
• T cell biology

Background:

• Novel immunosuppressive therapies aim to improve transplant efficacy and reduce toxicity.
• Belatacept, a CD28-CD80/86 inhibitor, offers benefits but is linked to higher rejection rates.
• Understanding belatacept-associated rejection mechanisms is crucial for its wider clinical use.

Purpose of the Study:

• To investigate the mechanisms underlying kidney transplant rejection in nonhuman primates treated with belatacept versus tacrolimus.
• To identify specific immune cell populations associated with belatacept-mediated rejection.

Main Methods:

• A nonhuman primate kidney transplant model was utilized.
• Animals received either a belatacept-based or a tacrolimus-based immunosuppressive regimen.
• Pre-transplant and post-transplant immune cell frequencies, including CD28+ CD8+ T_EMRA cells, were analyzed.

Main Results:

• Elevated pre-transplant CD28+ CD8+ T_EMRA cell frequencies correlated with rejection in belatacept-treated animals, but not in tacrolimus-treated ones.
• In rejecting allografts, CD28+ CD8+ T_EMRA cells rapidly lost CD28 expression post-transplant, with CD28- cells dominating the infiltrate.
• These findings suggest CD28+ memory T cells may be resistant to belatacept and can differentiate while retaining effector function.

Conclusions:

• CD28+ memory T cells exhibit resistance to belatacept therapy.
• These cells undergo differentiation, including CD28 loss, while maintaining effector function.
• Targeted therapies addressing the unique signaling of CD28+ memory T cells could synergize with belatacept to prevent costimulation-independent rejection.