IL-17A-producing γδ T cells and classical monocytes are associated with a rapid alloimmune response following vascularized composite allotransplantation in mice 3828

Description Vascularized Composite Allotransplantation (VCA) is an important therapeutic option for patients that incur debilitating and traumatic injuries to the face or limbs. The complexity and immunogenicity of tissue types within VCA grafts pose unique challenges and necessitate the use of intensive immunosuppression. However, current immunosuppressive protocols are not sufficient to effectively control graft rejection and are hampered by a poor understanding of the immune response following VCA. In this study, deep proteomic profiling and high dimensional analysis with cytometry time of flight (CyTOF) were used to define the unique cell types and mechanisms responding to VCA immunogenicity in BALB/c (H-2Kd) > C57BL/6 (H-2Kb) VCA recipients. In comparison to syngeneic transplant recipients, allogeneic recipients exhibited an early expansion of IL-17A-producing γδ T cells and patrolling monocytes followed by CD8+CD62L+ T cells and CD8+ effector/effector memory T cells (Teff/Tem) in secondary lymphoid tissues. Classical monocytes, CD4+ Teff/Tem, and CD8+ Teff/Tem were increased by day 5 post-transplant, with CD8+ Teff/Tem cells exhibiting the highest expression of IFN-γ, perforin, and granzyme B on day 7. Thus, we elucidated dynamic, coordinated alterations in T cell and monocyte populations associated with VCA allograft rejection. These findings will lead to more effective and precise treatment that will promote long-term survival of VCA grafts. Funding Sources T.T. was supported by the Stanford Transplant and Tissue Engineering Center of Excellence fellowship and the Overseas Research Fellowships of the Japan Society for the Promotion of Science (JSPS). This study was funded by Department of Defense grants RT190051 (S.M.K. & O.M.M.) and RT230036 (O.M.M. & S.M.K.). Topic Categories Transplantation Immunology (TRAN)