Memory T cells pose a significant problem to successful therapeutic control of unwanted immune responses during autoimmunity and transplantation， as they are differentially controlled by cosignaling receptors such as CD28 and CTLA-4. Treatment with abatacept and belatacept impede CD28 signaling by binding to CD80 and CD86， but they also have the unintended consequence of blocking the ligands for CTLA-4， a process that may inadvertently boost effector responses. Here， we show that a potentially novel anti-CD28 domain antibody (dAb) that selectively blocks CD28 but preserves CTLA-4 coinhibition confers improved allograft survival in sensitized recipients as compared with CTLA-4 Ig. However， both CTLA-4 ... More
Memory T cells pose a significant problem to successful therapeutic control of unwanted immune responses during autoimmunity and transplantation， as they are differentially controlled by cosignaling receptors such as CD28 and CTLA-4. Treatment with abatacept and belatacept impede CD28 signaling by binding to CD80 and CD86， but they also have the unintended consequence of blocking the ligands for CTLA-4， a process that may inadvertently boost effector responses. Here， we show that a potentially novel anti-CD28 domain antibody (dAb) that selectively blocks CD28 but preserves CTLA-4 coinhibition confers improved allograft survival in sensitized recipients as compared with CTLA-4 Ig. However， both CTLA-4 Ig and anti-CD28 dAb similarly and significantly reduced the accumulation of donor-reactive CD8+ memory T cells， demonstrating that regulation of the expansion of CD8+ memory T cell populations is controlled in part by CD28 signals and is not significantly impacted by CTLA-4. In contrast， selective CD28 blockade was superior to CTLA-4 Ig in inhibiting IFN-γ， TNF， and IL-2 production by CD8+ memory T cells， which in turn resulted in reduced recruitment of innate CD11b+ monocytes into allografts. Importantly， this superiority was CTLA-4 dependent， demonstrating that effector function of CD8+ memory T cells is regulated by the balance of CD28 and CTLA-4 signaling.
