Dataset Information


Selective CD28 blockade attenuates CTLA-4-dependent CD8+ memory T cell effector function and prolongs graft survival.

ABSTRACT: 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-?, 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.


PROVIDER: S-EPMC5821191 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2019-01-01 | S-EPMC6658342 | BioStudies
2020-01-01 | S-EPMC7096747 | BioStudies
2017-01-01 | S-EPMC5590720 | BioStudies
2014-01-01 | S-EPMC4124942 | BioStudies
2014-01-01 | S-EPMC4071624 | BioStudies
2015-01-01 | S-EPMC4628789 | BioStudies
2017-01-01 | S-EPMC5573634 | BioStudies
1000-01-01 | S-EPMC3017182 | BioStudies
2011-01-01 | S-EPMC3057516 | BioStudies
2016-01-01 | S-EPMC4769294 | BioStudies