title: Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation.
abstract: Inflammation in the priming host environment has critical effects on the graft-versus-host (GVH) responses mediated by naive donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show in this article that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared with naive T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation, and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared with freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-γ dependent. TLR stimulation after transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for graft-versus-host disease and T cell-mediated immunotherapies.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032; Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129;
authors.forename: Hao Wei
authors.initials: HW
authors.lastname: Li
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129;
authors.forename: Giovanna
authors.initials: G
authors.lastname: Andreola
authors.affiliation: Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114; and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Alicia L
authors.initials: AL
authors.lastname: Carlson
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032;
authors.forename: Steven
authors.initials: S
authors.lastname: Shao
authors.affiliation: Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114; and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032; Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129;
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032; Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129; Megan.Sykes@columbia.edu.
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D005260:Female; D006087:Graft vs Host Reaction / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D011828:Radiation Chimera / Q000276:immunology
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma