Allogeneic Effector Memory T Cells Enhance Hematopoietic Engraftment and Immune Reconstitution After Stem Cell Transplantation
Authors: Zhang Jifeng , DeOliveira Divino , Son Jessica , Cui Xiuyu , Chao Nelson J. , Chen Benny J. 
Published: October 2019

Abstract
Abstract 78
Allogeneic effector memory T Cells (TEM) are able to kill host radioresistant T cells and host-type tumor cells without causing GVHD, suggesting that allogeneic TEM may facilitate hematopoietic engraftment. We investigated the effects of allogeneic TEM on hematopoietic engraftment and immune reconstitution using a rejection model. TEM were prepared after negative selection of T cells followed by depletion of CD62L+ cells using magnetic beads. Lethally irradiated (8.5Gy) BALB/c mice were transplanted with minimum number (5×105) of C57BL/6 T cell depleted bone marrow (TCD BM) cells. Only 40% of TCD BM recipients survived more than 100 days after transplantation. In contrast, addition of donor TEM in the stem cell graft rescued 90% of the recipients (P<0.01, compared with TCD BM alone group). While all the recipients receiving TCD BM alone were mixed chimera (37.6±14.6% donor), all the recipients of additional donor TEM became full chimera (99.7±0.07% donor). These data suggest that facilitation of engraftment is likely due to donor TEM activation. Upon transfer into BALB/c recipients, donor TEM were activated, secreted multiple inflammatory cytokines, and expressed all known cytotoxic molecules. Facilitation of engraftment may also lead to enhanced immune reconstitution. Faster stem-cell-derived T cell generation was observed in allogeneic TEM recipients compared with the recipients of stem cells (c-Kit+ Thy1.1low Lin− Sca-1+) alone (P<0.01). Enhancement of stem-cell-derived T cell reconstitution was dramatically decreased in SCID recipients (lacking T and B cells) and could not be observed in NOG recipients (lacking T, B, and NK cells), further indicating that allogeneic TEM enhance immune reconstitution through depletion of host radioresistant immune cells. To confirm that allogeneic TEM enhance functional immune reconstitution, we injected BCL1 cells to the recipients at day +7 after transplantation. While 6 out of 8 C57BL/6 TCD BM alone recipients died of tumor, all allogeneic TEM recipients were tumor-free and survived more than 100 days after transplantation (P<0.001). We hypothesize that donor TEM can react to alloantigens initially but the alloresponses can not be sustained upon transfer to GVHD recipients, thus explaining the dichotomy of lack of GVHD with preservation of GVL. To test this hypothesis, we injected BCL1 cells into lethally irradiated BALB/c recipients of Rag-2−/−gC−/− BM and TEM from C57BL/6 mice at different time points (day +7, +14, +21, +28) after transplantation. When injected at day +7, allogeneic TEM recipients survived significantly longer than Rag-2−/−gC−/− BM only controls (medium survival time: 66 days vs. 26 days). When injected after day +14, the development of tumor and survival were comparable between Rag-2−/−gC−/− BM only and allogeneic TEM groups. These data demonstrate that allogeneic TEM enhance hematopoietic engraftment and immune reconstitution by reducing host resistance. The activation of allogeneic TEM does not lead to GVHD because the alloresponse induced by TEM can not be sustained in allogeneic stem cell recipients.

Disclosures:
No relevant conflicts of interest to declare.