Kidney Week

Abstract: FR-OR122

Tissue Resident Memory T Cells in Mouse Renal Transplantation

Session Information

• Transplantation: Basic Research
  November 08, 2019 | Location: 150, Walter E. Washington Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Transplantation

• 1901 Transplantation: Basic

Authors

• Abou Daya, Khodor, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Khodor Abou Daya, MD

• Oberbarnscheidt, Martin H., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Martin H. Oberbarnscheidt,

• Lakkis, Fadi G., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Fadi G. Lakkis,

Background

The newly identified tissue resident subset of memory T cells (T_RM) provides immune surveillance in the tissue and first response against infections. They are functionally, transcriptionally, and phenotypically distinct from circulating effector and central memory T cells. The role of T_RM in transplantation is unknown. In this study, we investigated the formation and function of T_RM in a mouse kidney transplantation model.

Methods

Syngeneic B6 or allogeneic (B6xBALB/c) F1.ova kidneys were transplanted to B6 recipients and 1 million OT-I effector T cells were transferred on day 2. Graft, blood, bone marrow, SLO, and liver tissues were harvested 4 and 8 wks after transplantation. Serum creatinine was measured using i-Stat analyzer. T_RM were identified phenotypically as CD44^hiCD62L^lowCD69⁺ CD103^+/- cells after excluding in vivo labeled T cells. OT-I and polyclonal T_RM were transcriptional characterized using scRNAseq. We tested T_RM residency in the graft by performing parabiosis between 4-wk transplanted CD45.1 B6 mice that contained OT-I effectors and CD45.2 B6 parabionts that had received F1.ova kidneys but no OT-I. Whether T_RM are sufficient for rejection was tested in a re-transplantation model using splenectomized LTBR-/- mice as secondary recipients of F1.ova grafts containing T_RM. Depletion experiments are underway to further establish causal relationship between T_RM and rejection.

Results

Mean serum creatinine (mg/dl) was significantly higher in allogeneic vs syngeneic group at wk 8 (0.8 vs 0.2, p<0.05). Graft histology showed mixed acute and chronic rejection in the allogeneic group. Flow analysis of allograft cells demonstrated T_RM cells among OT-I and endogenous T cell populations at 4 & 8 wks. The OT-I population was exclusively T_RM phenotype by flow and scRNAseq, rapidly produced IFNg upon re-stimulation, and was not detected anywhere else. There was no significant difference in mean number of OT-Is between wk 4 and wk 8 (125k vs 79k, p=0.94). OT-I T cells could not be detected in the parabiont kidney graft or tissues or in the secondary host outside the re-transplanted kidney, indicating that the T_RM are indeed resident in the graft and do not re-circulate. Chronic rejection progressed in re-transplanted kidneys that harbored T_RM.

Conclusion

Our findings show that donor-specific T_RM form in kidney allografts, are functional, and could contribute to rejection.

Funding

• Other NIH Support