Tissue-resident memory T cells of donor origin are short-lived in renal allografts after transplantation

K. de Leur, M. Dieterich, O.B.J. Corneth, G.N. de Graav, A. Mulder, F.J.M.F. Dor, H.J.A.N. Kimenai, F.H.J. Claas, D.A. Hesselink, M.C. Clahsen-van Groningen, L.J.W. van der Laan, R.W. Hendriks, C.C. Baan

Thursday 15 march 2018

16:55 - 17:05h at Van Weelde Zaal

Categories: Basic / translational research, Session (parallel)

Parallel session: Parallel session 7: Basic / translational research

Introduction

Tissue-resident memory T (T_RM) cells provide protective immunity by rapidly responding to antigen in non-lymphoid tissues. These non-migrating memory T cells are characterized by surface expression of CD69 and CD103. In transplanted kidneys the existence and properties of T_RM cells are unclear. In this study, we used the unique tissue resource of transplant nephrectomies to determine whether T_RM cells reside in rejected kidney allografts and whether these cells are of donor or recipient origin.

Materials and methods

Thirteen transplant nephrectomy specimens were studied. These grafts failed because of acute (n=4) or chronic (n=9) rejection and were removed after a mean time of 6.7 years (range: 8 days – 26 years). Half of the renal allograft was processed into a single cell suspension and analyzed by flow cytometry. The origin of the cells was measured by mAb directed against HLA epitopes of the donor or acceptor.

Results

Functional CD3+ T cells were isolated from all explanted kidney allografts as 57.8±16.5% (mean ± SD) of the cells had the capacity to produce IFNγ; 16.1±6.8% produced IL-2; 1.8±1.2% IL-17, and 4.6±5.2% IL-4 after re-stimulation. The isolated T cells consisted of 43.2±19.1% CD4+ T cells and 45.3±20.6% CD8+ T cells.

Of the CD8+ T cells, 27.9±15.5% expressed CD69 and CD103, reflecting CD8+ T_RM cells. The majority of these T_RM cells did not express CD28 (61.6±18.2%), indicating a phenotype associated with highly-reactive effector functions. The isolated CD4+ T cells included a relatively small population of T_RM cells (1.9±2.2%). We confirmed that T_RM cells were exclusively present in the renal allografts and not in the circulation of healthy controls (p=0.002). No differences in proportions of T_RM cells were found between acute and chronically rejecting kidney allografts.

High proportions of donor T cells were present in the renal allografts removed within the first month after transplantation (6.8±5.7% CD4+; 9.8±9.2% CD8+ T cells) compared to low proportions in the renal allografts removed after one month (0.4±0.3% CD4+; 0.3±0.3% CD8+ T cells). Remarkably, within the CD8+ T_RM cells the ratio between donor versus recipient cells was 3.6 times higher compared to this ratio within the total CD8+ T cells.

Conclusion

Our results demonstrate that both donor and patient CD4+ and CD8+ T_RM cells reside in the rejecting transplanted kidney. Over time, the donor T_RM cells disappear from the allograft.