title: Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGVHD) is an increasingly common cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Relative to acute GVHD (aGVHD), much less is understood about cGVHD. Using the B10.D2 --> BALB/c murine cGVHD model, which shares critical pathologic features with human cGVHD, we find that radiation-resistant host T cells regulate cGVHD. We initially observed that recipients lacking all lymphocytes developed accelerated and more severe cGVHD. Using genetically deficient recipients, we determined that alphabeta+CD4+ T cells were required to regulate cGVHD. Increased cGVHD severity was not due to the absence of T cells per se. Rather, the potency of regulation was proportional to host T-cell receptor (TCR) diversity. Only CD4+CD25+, and not CD4+CD25-, host T cells ameliorated cGVHD when added back, indicating that host T cells acted not via host-versus-graft activity or by reducing homeostatic proliferation but by an undefined regulatory mechanism. Thus, preparative regimens that spare host CD4+CD25+ T cells may reduce cGVHD. Donor CD4+CD25+ T cells also reduced cGVHD. Depletion of CD4+CD25+ cells from the inoculum exacerbated disease, whereas transplantation of additional CD4+CD25+ cells protected against severe cGVHD. Additional CD4+CD25+ cells also promoted healing of established lesions, suggesting that their effects persist during the evolution of cGVHD.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar St, PO Box 208035, New Haven, CT 06520-8035, USA.
authors.forename: Britt E
authors.initials: BE
authors.lastname: Anderson
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: McNiff
authors.forename: Catherine
authors.initials: C
authors.lastname: Matte
authors.forename: Ionna
authors.initials: I
authors.lastname: Athanasiadis
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D002470:Cell Survival / Q000276:immunology / Q000528:radiation effects; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D015704:CD4 Antigens; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; C064655:V(D)J recombination activating protein 2