title: CD4 T Cell Help via B Cells Is Required for Lymphopenia-Induced CD8 T Cell Proliferation.
abstract: Ab-mediated lymphoablation is commonly used in solid organ and hematopoietic cell transplantation. However, these strategies fail to control pathogenic memory T cells efficiently and to improve long-term transplant outcomes significantly. Understanding the mechanisms of T cell reconstitution is critical for enhancing the efficacy of Ab-mediated depletion in sensitized recipients. Using a murine analog of anti-thymocyte globulin (mATG) in a mouse model of cardiac transplantation, we previously showed that peritransplant lymphocyte depletion induces rapid memory T cell proliferation and only modestly prolongs allograft survival. We now report that T cell repertoire following depletion is dominated by memory CD4 T cells. Additional depletion of these residual CD4 T cells severely impairs the recovery of memory CD8 T cells after mATG treatment. The CD4 T cell help during CD8 T cell recovery depends on the presence of B cells expressing CD40 and intact CD40/CD154 interactions. The requirement for CD4 T cell help is not limited to the use of mATG in heart allograft recipients, and it is observed in nontransplanted mice and after CD8 T cell depletion with mAb instead of mATG. Most importantly, limiting helper signals increases the efficacy of mATG in controlling memory T cell expansion and significantly extends heart allograft survival in sensitized recipients. Our findings uncover the novel role for helper memory CD4 T cells during homeostatic CD8 T cell proliferation and open new avenues for optimizing lymphoablative therapies in allosensitized patients.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Ayasoufi
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Ran
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and Glickman Urological Institute, Cleveland Clinic, Cleveland, OH 44195 valujsa@ccf.org.
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D064591:Allografts; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D016027:Heart Transplantation; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018183:Transplantation Chimera
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand