Patients who receive an organ transplant often experience more than the restoration of their health; they can enjoy their favorite foods once again or even run marathons. Yet, despite an initially successful transplant, several factors may eventually result in chronic rejection, leading to organ failure (1).
The transplant recipient’s immune system is one of the key players in the long-term success of the intervention. In particular, a subset of the recipient’s memory T cells that form in the transplanted organ may contribute to chronic rejection (2). In a recent study published in Science Immunology, researchers explored the factors modulating the activity of these tissue-resident memory T (TRM) cells in a mouse model of kidney transplantation (3). They found that activity of the inflammatory cytokine interleukin-15 (IL-15) is important for these cells’ maintenance. When researchers inhibited IL-15, the new organ survived six months after transplantation, while in most untreated mice, the organ failed after four months.
For Laura Mackay, an immunologist at the University of Melbourne who did not participate in this study, the research showed promise for treatment development. “You can modulate tissue-specific T cells to prevent chronic rejection,” she said.
Under ordinary circumstances, TRM cells provide tissues with rapid protection against pathogens that they’ve encountered before. “You don't have to wait for that infiltration of circulating T cells to come back into the tissue, which is often too late with a viral infection,” said Mackay.
In organ transplants, however, the defensive ability of the noncirculating T cells may bring trouble.
“When we began these studies, we didn’t know if tissue-resident memory T cells would even form in the setting of transplantation,” said Martin Oberbarnscheidt, a transplant immunologist at the University of Pittsburgh and coauthor of the new study. But in 2021, he and his colleagues reported that effector T cells differentiate into TRM cells in transplanted kidneys in mice and that they contributed to allograft rejection (2).
The next question was how the body maintains these cells in the transplanted organs. “It’s important because once we know what makes them stay in the tissue, maybe we can devise methods to get rid of them,” Oberbarnscheidt noted.
The team first investigated whether the continuous presence of the antigen itself — those molecules in the donor organ that T cells identify as foreign — is necessary for the maintenance of the TRM cells. Previous studies have yielded mixed results as to whether sustained antigen exposure is necessary for maintaining the activity of these cells in viral infections (4,5), and in the context of allograft tissue, this had never been studied. In their mouse model, Oberbarnscheidt and his colleagues found that the persistent interaction between TRM cells and the antigen within the tissue was indeed required for TRM cell maintenance.
Since it’s not currently possible to remove the offending antigens from the transplanted organ, the team next investigated what other elements maintain the functionality of these cells within the graft. Their main candidate was IL-15, an inflammatory cytokine essential for maintaining memory T cells and required for TRM cell survival in the context of viral infection (6). To test its role in chronic organ rejection, the researchers treated the transplant recipients with an anti-CD122 antibody, which blocks IL-15 signaling, three times weekly for a period of two weeks. The treatment significantly reduced the number of TRM cells in the transplanted kidney when compared to the number in untreated mice.
We achieved long-term graft survival without any rejection in mice, and we saw a reduction of these tissue-resident memory T cells in the graft.
- Martin Oberbarnscheidt, University of Pittsburgh
Extending this antibody treatment for the 182-day study period resulted in a remarkable increase of graft survival. The transplanted kidneys of all six mice that received the anti-CD122 treatment survived six months after transplantation, whereas the researchers only saw such survival extension in one of the seven untreated mice.
The anti-CD122 antibody’s capacity to modulate TRM cells has previously shown favorable outcomes for potentially treating other diseases, for instance, vitiligo (7). However, Mackay noted that for organ rejection, systemic blockade of IL-15 may have downstream consequences. Therefore, this approach requires the development of more TRM-specific therapies, which many researchers are currently working on, she said.
While Oberbarnscheidt acknowledged that further work is needed to assess the potential toxicity and other side effects of the approach, he added that these initial results are encouraging. “What was very promising in using this antibody was that we achieved long-term graft survival without any rejection in mice, and we saw a reduction of these tissue-resident memory T cells in the graft,” he said. If this outcome is mirrored in studies in nonhuman primates and, ultimately, in clinical trials, this strategy could one day be life-changing for transplant recipients in the long term.
- Chronic transplantation rejection. StatPearls - NCBI bookshelf at https://www.ncbi.nlm.nih.gov/books/NBK535435/
- Abou-Daya, K.I. et al. Resident memory T cells form during persistent antigen exposure leading to allograft rejection. Sci Immunol 6, eabc8122 (2021).
- Tieu, R. et al. Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15. Sci Immunol 8, eadd8454 (2023).
- Mackay, L.K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. PNAS 109, 7037–7042 (2012).
- Khan, T.N. et al. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J Exp Med 213, 951-966 (2016).
- Mackay, et al. T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity 43, 1101-11 (2015).
- Richmond, J.M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med 18, eaam7710 (2018).