Selective CD28 blockade attenuates CTLA-4-dependent CD8+ memory T cell effector function and prolongs graft survival
| Autor: | Mandy L. Ford, Danya Liu, I. Raul Badell |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Graft Rejection
T-Lymphocytes chemical and pharmacologic phenomena 030230 surgery CD8-Positive T-Lymphocytes Belatacept Abatacept 03 medical and health sciences Mice 0302 clinical medicine Immune system CD28 Antigens medicine Animals CTLA-4 Antigen CD86 Transplantation Chemistry Graft Survival CD28 hemic and immune systems General Medicine Allografts Immunity Innate Cell biology Mice Inbred C57BL medicine.anatomical_structure CTLA-4 Models Animal B7-1 Antigen Cytokines B7-2 Antigen Memory T cell Immunologic Memory CD80 CD8 030215 immunology medicine.drug Research Article |
| Zdroj: | JCI insight. 3(1) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|