Challenges and opportunities in targeting the CD28/CTLA-4 pathway in transplantation and autoimmunity

ABSTRACT

Introduction: T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86.

Areas covered: This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies.

Expert opinion: The development of CD28 blockers Abatacept and Belatacept provided a more targeted therapy approach for transplant rejection and autoimmune disease relative to calcineurin inhibitors and anti-proliferatives, but overall efficacy may be limited due to their collateral effect of simultaneously blocking CTLA-4 coinhibitory signals. As such, current investigations into the potential of selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4 are promising. However, as selective CD28 blockade inhibits the activity of both effector and regulatory T cells, an important goal for the future is the design of therapies that will maximize the attenuation of effector responses while preserving the suppressive function of T regulatory cells.

KEYWORDS:

• T cell biology
• costimulation
• coinhibitory signaling
• transplantation
• autoimmunity
• monoclonal antibodies

Article Highlights

• CD28 costimulation blockade is advantageous for inhibiting unwanted T cell responses during autoimmunity and transplantation because the targets are confined to the immune system, limiting off-target toxicities associated with calcineurin inhibitors and anti-proliferatives

• Blocking CD28 using conventional CTLA-4 Ig fusion proteins (abatacept, belatacept) that bind to the shared receptors CD80/CD86 has the collateral effect of also inhibiting CTLA-4 coinhibitory signaling

• Due to both relative CD28 independence and the loss of regulation via CTLA-4 coinhibitory signals, memory T cells, Th17 cells, and impaired Treg function may play a role in breakthrough T cell responses in patients treated with CTLA-4Ig fusion proteins

• Novel CD28-specific domain antibodies have been developed in order to selectively block CD28 signals while leaving CTLA-4 coinhibitory signaling intact

• Inhibition of CD28 signals on Foxp3⁺ Treg populations may still pose a challenge for the use of selective CD28 blocking reagents in transplantation and autoimmunity

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Declaration of interest

M Ford has received honoraria from Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

ML Ford is supported by National Institute of Allergy and Infectious Diseases (NIAID) grants AI104699 and AI073707 while RL Crepeau is supported by NIAID grant AI070081.