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Resident memory T cells form during persistent antigen exposure leading to allograft rejection

ABSTRACT: Tissue resident memory T cells (TRM) contained at sites of previous infection provide local protection against re-infection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long-term in allografts, but it is not known whether they are exhausted or are functional memory T cells. Using a mouse model of kidney transplantation, we showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subqeuntly caused allograft rejection. TRM identity was established by surface phenotype, transcriptional profile, and inability to recirculate in parabiosis and re-transplantation experiments. Graft TRM proliferated locally, produced IFNγ upon re-stimulation, and their in vivo depletion attenuated rejection. Importantly, the vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE166166 | GEO | 2021/03/20

REPOSITORIES: GEO

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