After MHC-matched allografting, host-derived langerhans cells (LCs) persist in skin and cutaneous lymph nodes in the steady-state and are the targets of DLI-mediated alloresponse

Abstract

The mechanisms that govern T cell-mediated alloresponses in the post-transplant setting, particularly T cell-dendritic cell (DC) interactions, are critical for developing strategies to augment their antitumor effects and limit toxicity such as GVHD. We hypothesize that kinetics of DC reconstitution and the number of host DCs persisting in various lymphoid tissues after alloBMT may differ and if characterized, may be relevant in guiding T cell alloresponses following transplant. To analyze DC reconstitution inthe MHC-matched setting, we used a B6Ly 5.2 (H2b ; CD45.1+)→ C3H.SW (H2b ; CD45.2+) model that differs in expression of the CD45 marker on host and donor hematopoietic tissues. We found that the donor to host DC turnover is rapid with near full conversion to donor DC chimerism in the spleen and mesenteric lymph nodes but not in the cutaneous lymph nodes (CLNs). The dominant residual host DC population in LNs is characterized by the low expression of CD8+ but high expression of DEC-205 and gp40 (Ep-CAM), the profile completely consistent with the phenotype of LCs. We reproducibly detected residual host-derived LCs in the chimeras CLNs for at least 6 months after alloBMT and found them to constitutively express an activated phenotype. Levels of expression of the costimulatory molecules, CD80, CD40, and especially CD86 on host-derived LCs was actually higher in comparison to donor-derived LCs. The skin origin of host-derived DCs in LNs was confirmed by analysis of CD11c+ that migrate out of ex vivo cultured epidermal sheets. Because the majority of the CD11c+ was of host origin, this suggests that alloresponse against minor histocompatibility antigens is not sufficient enough to cause LC replacement. The persistence of residual host LCs after alloBMT prompted us to determine whether they serve as the target of the DLI-mediated alloresponse. Administration of DLI 3 weeks after conditioning resulted in the decrease of residual host-derived LCs in the CLNs and recruitment of donor derived LCs to the skin. Our data suggest the following: (a) After myeloablative conditioning and transplantation of MHC-matched marrow, there is a rapid replacement of secondary lymphoid organs with donor marrow-derived DCs but that the significant amount of skin DCs are of host origin ; (b) during steady-state conditions after alloBMT, host-derived LCs bearing an activated phenotype are continuously present in the CLNs ; and (c) host-derived LCs are the targets of the DLI-mediated alloresponse.