Targeting CD122, which has an important role in both primary and secondary immune responses, has the potential to reduce transplant rejection, say researchers.

Credit: Lara Crow/Springer Nature Limited

Immunosuppressive therapies are effective at preventing early rejection in transplant recipients, but late rejection and adverse effects are common. Blocking T cell-co-stimulatory pathways is a more targeted approach and belatacept, a high-affinity version of cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA4–Ig), which blocks ligand ligation to CD28, is approved in kidney transplant recipients. However, belatacept is associated with increased early rejection in some patients.

“Our work has been to determine which pathways are important for T cell-mediated rejection in the absence of co-stimulatory signals — so-called co-stimulation-independent rejection,” says Andrew Adams, an author on the new paper. “CD122 is an important component of the IL-2–IL-15 receptor complex. Both IL-2 and IL-15 are critical cytokines for T cell development and function. We hypothesized that co-stimulation-independent T cells may rely on signals from these cytokines.”

Using a mouse model of transplantation, the researchers showed that CD122 was important for both naive T cell function and for memory T cells. Adams and colleagues also investigated the CD122 pathway in rhesus macaques.

treatment with an antibody specific for CD122 was able to prevent co-stimulation-independent rejection

“We were able to show that in the absence of traditional co-stimulatory signals, IL-2 was important for naive T cell responses whereas IL-15 played a critical role in memory-dependent rejection,” notes Adams. “As CD122 is required for both IL-2 and IL-15 signalling, treatment with an antibody specific for CD122 was able to prevent co-stimulation-independent rejection. Currently, many kidney transplant recipients only receive therapy directed against the IL-2 specific receptor (CD25) and when used in conjunction with belatacept results in high rejection rates. Our data suggest that by blocking both naive and memory T cells (IL-2 and IL-15), anti-CD122 therapy may be combined with belatacept to provide improved survival with low rejection rates.”