Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival
Danya Liu, I. Raul Badell, Mandy L. Ford
Danya Liu, I. Raul Badell, Mandy L. Ford
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Research Article Immunology Transplantation

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-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.

Authors

Danya Liu, I. Raul Badell, Mandy L. Ford

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Figure 2

Selective CD28 blockade more potently attenuates the accumulation of donor-reactive CD8+ T cells following transplantation as compared with CTLA-4 Ig.

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Selective CD28 blockade more potently attenuates the accumulation of don...
(A) Thy1.1+ OT-I T cells (1 × 104)were adoptively transferred into naive B6 Thy1.2 hosts and infected with Listeria-OVA to generate recipients containing memory OT-I T cells. On day 30 after infection, mice received an OVA-expressing skin graft and were treated with 200 μg CTLA-4 Ig or 100 μg anti-CD28 dAb on days 0, 2, 4, and 6 after transplant. Animals were sacrificed on days 5 or 10 after transplant and graft-draining LN were harvested; the number of Thy1.1+ CD8+ T cells was quantified in (B) representative flow cytometry plots and (C and D) summary data of absolute number of CD8+Thy1.1+ T cells per draining node on day 5 (C) and day 10 (D). (E) MFI of ICOS, CD44, and CD62L expression on CD8+Thy1.1+ T cells isolated from LN of mice in the indicated groups. Box and whisker plots show the median value. Boxes represent the 25th and 75th percentile, and whiskers depict the minimum and maximum values. Data shown in C–E are representative of data of 3 independent experiments with a total of 10–15 mice per group. (F) Endogenous OVA-specific CD8+ T cell responses were measured on day 5 after transplant in the spleen in mice treated as above with either CTLA-4 Ig or anti-CD28 dAb (or left untreated). BrdU was administered on days 2 and 4 as described in Methods, and data shown are gated on CD8+Thy1.1– splenocytes. (G) Summary data from F depicting n = 5 mice per group. Experiment shown is representative of 2 independent experiments with a total of 9–10 mice per group. *P < 0.05 05 by 1-way ANOVA. dAb, domain antibody.