Recipient-derived, graft-specific memory T cells play a critical role in mediating allograft rejection, particularly in the setting of immunosuppression with costimulation blockade. Recently, it is increasingly well-appreciated that non-lymphoid tissues, such as skin, lung and gut, harbor substantial populations of resident memory T (TRM) cells, which provide local and compartmentalized immunity. Seminal studies over the last year have further revealed that in addition to these organs that contact the environment, organs such as kidney and liver also contain large numbers of CD103+ CD69+ TRM that are likely carried over into the recipient upon transplantation. Owing to the process of heterologous immunity, it is possible that these donor-derived TRM populations could contain T cells that are alloreactive against recipient antigens. Given this paradigm, we sought to determine the role of donor-derived, recipient-specific TRM in transplant rejection. We established a model in which skin tissue obtained from sensitized animals, containing donor-derived, host-reactive TRM, was used to graft naïve recipients. Specifically, BALB/c mice receiving a full-thickness B6 skin graft were allowed to reject. Twenty-one days later, congenically marked naïve B6 hosts received grafts from either these B6-sensitized BALB/c animals, or from non-sensitized naïve BALB/c controls. Animals were treated with CTLA-4 Ig and anti-CD154 costimulation blockade and monitored for allograft rejection. We found that mice receiving B6-sensitized BALB/c skin allografts underwent accelerated rejection relative to controls that received non-sensitized donor skin, suggesting that the presence of donor-derived, host-reactive TRM within the graft enhanced graft-specific alloimmunity. To address the mechanism underlying this observation, we interrogated the graft-specific CD8+ T cell responses in the draining LN of animals receiving sensitized vs. non-sensitized allografts. Intriguingly, we found that mice receiving B6-sensitized BALB/c skin grafts possessed increased frequencies of CD44hi activated T cells within their CD8+ T cell compartments at day 7 in the draining LN. These data suggest that memory T cells residing within transplanted organs may potentiate donor-specific alloimmunity. Further studies are warranted to understand the clinical impact of donor-derived, host-reactive TRM cell alloreactivity and to investigate strategies to attenuate their ability to enhance and accelerate alloaggressive immune responses following transplantation.

CITATION INFORMATION: Crepeau R, Liu D, Ford M. Role of Donor-Derived Tissue Resident Memory T cells in Modulating Alloimmunity. Am J Transplant. 2017;17 (suppl 3).

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