Journal
JCI INSIGHT
Volume 3, Issue 1, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.96378
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Funding
- NIH [AI104699, AI073707]
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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-gamma, 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.
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