Date: Tuesday, May 5, 2015
Session Time: 2:15pm-3:45pm
Presentation Time: 2:15pm-2:27pm
Location: Room 118-C
The underlying mechanisms by which distinct NK cell subsets promote either allograft rejection or survival remain unclear. Here, we tested the hypothesis that distinctively mature NK cell subsets control alloreactive T cell responses through their interactions with graft-derived donor DCs.
We used BALB/c.Rag-T-bet double-KO (DKO) mice that lack terminally-differentiated CD27low NK cells to study the role of mature CD27low NK cells in a model of T cell-mediated allograft rejection. For this, Rag-T-bet DKO and Rag-KO recipients of fully mismatched B6 skin allografts (STx) were adoptively transferred with purified T cells from Foxp3-gfp-knock-in BALB/c mice and treated with costimulatory blockade (CTLA4Ig and MR-1). Groups of recipients received a STx from B6.IL-15-KO and B6.CD11c-DTR donors. Alloimmune responses were analyzed by histology, ELISA, RT-PCR and flow cytometry.
Costimulatory blockade-treated Rag-KO recipients (with CD27low NK cells) showed significantly prolonged allograft survival (MST 35±3d, P<0.001) and reduced alloreactive CD8+ T cell responses (ELISA, flow cytometry) when compared to DKO mice lacking CD27low NK cells (28±1d). Next, we discovered that Rag-KO recipients with CD27low NK cells show significantly lower IL-15 serum levels (2.24 fold) versus Rag-T-bet DKO recipients (ELISA), suggesting that CD27low NK cells control graft-derived IL-15, thereby inhibiting alloreactive CD8+ T cell responses and promoting allograft survival. To test this we grafted Rag-T-bet DKO recipients with STx from IL-15-KO donors and found significantly longer allograft survival (39±2d vs 28±1d, P<0.05) and reduced CD8+ T cell responses in the absence of IL-15. Therefore, we hypothesized that host CD27low NK cells control graft-derived donor DCs, which are known to express high levels of IL-15. To test this we grafted Rag-T-bet DKO recipients with STx from CD11c-DTR mice that were depleted from CD11c+ DCs via diphtheria toxin. Importantly, the lack of donor DCs in STx significantly prolonged allograft survival (50±4d vs 28±1d) and dramatically reduced alloreactive CD8+ T cell responses in DKO recipients.
Therefore, under costimulatory blockade conditions mature CD27low NK cells control IL-15-expressing graft-derived donor DCs, which inhibits alloreactive CD8+ T cell responses and promotes allograft survival.
To cite this abstract in AMA style:Kroemer A, Lantow M, Eggenhofer E, Sabet-Baktach M, Renner P, Schlitt H, Geissler E. CD27low NK Cells Prolong Allograft Survival in Mice By Inhibiting CD8+ T Cell Responses Through Controlling Graft-Derived Donor DCs [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/cd27low-nk-cells-prolong-allograft-survival-in-mice-by-inhibiting-cd8-t-cell-responses-through-controlling-graft-derived-donor-dcs/. Accessed February 26, 2020.
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