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

Area of Science:

• Immunology
• Transplantation Immunology
• Autoimmunity

Background:

• Memory T cells are key targets for controlling immune responses in autoimmunity and transplantation.
• Current therapies like CTLA-4 Ig block CD28 and CTLA-4 ligands, potentially boosting unwanted effector responses.
• Differential control of T cell costimulation via CD28 and CTLA-4 is critical for immune regulation.

Purpose of the Study:

• To investigate a novel anti-CD28 domain antibody (dAb) for selective CD28 blockade.
• To compare the efficacy of selective CD28 blockade versus CTLA-4 Ig in allograft survival and T cell regulation.
• To elucidate the roles of CD28 and CTLA-4 signaling in regulating CD8+ memory T cell function and innate immune cell infiltration.

Main Methods:

• Development and testing of a novel anti-CD28 domain antibody (dAb).
• Comparison of anti-CD28 dAb with CTLA-4 Ig in a sensitized recipient allograft survival model.
• Analysis of donor-reactive CD8+ memory T cell accumulation and cytokine production (IFN-γ, TNF, IL-2).
• Assessment of innate CD11b+ monocyte recruitment into allografts.

Main Results:

• The anti-CD28 dAb demonstrated improved allograft survival compared to CTLA-4 Ig in sensitized recipients.
• Both anti-CD28 dAb and CTLA-4 Ig reduced CD8+ memory T cell accumulation, indicating CD28's role in T cell expansion.
• Selective CD28 blockade was superior in inhibiting CD8+ memory T cell effector functions (IFN-γ, TNF, IL-2 production).
• This enhanced inhibition of effector function by anti-CD28 dAb led to reduced monocyte infiltration into allografts.

Conclusions:

• Selective blockade of CD28, while preserving CTLA-4 coinhibition, offers a superior therapeutic strategy for allograft survival.
• CD28 signaling plays a significant role in the expansion of CD8+ memory T cells.
• The balance between CD28 and CTLA-4 signaling is crucial for regulating the effector function of CD8+ memory T cells and subsequent innate immune cell recruitment.