Accelerated onset and increased severity of acute graft-versus-host disease following adoptive transfer of DR6-deficient T cells.
DR6 is a recently identified member of the TNFR family. In a previous study, we have shown that DR6 KO mice have enhanced CD4(+) T cell proliferation and Th2 cytokine production. Acute graft-vs-host disease (GVHD) results from the activation and expansion of alloreactive donor T cells following bone marrow transplantation. In this article, we demonstrate that the transfer of donor T cells from DR6 KO mice into allogeneic recipient mice in a parent into an F(1) model of acute GVHD results in a more rapid onset of GVHD with increased severity. Recipients of DR6 KO T cells exhibit earlier systemic symptoms of GVHD, more rapid weight loss, earlier histopathological organ damage in the thymus, spleen, and intestines, and earlier mortality. The rapid onset of GVHD in these mice may be attributable to the enhanced activation and expansion of DR6 KO CD4(+) and CD8(+) T cells. Our findings support the hypothesis that DR6 serves as an important regulatory molecule in T cell immune responses. The identification and use of DR6 ligands and/or agonistic Abs to DR6 may represent useful therapeutics in the treatment of T cell-mediated diseases such as GVHD.
Liu
Jinqi
J
Department of Bio-Research Technologies and Proteins, Eli Lilly, Lilly Corporate Center, MC625, Indianapolis, IN 46285, USA.
Heuer
Josef G
JG
Na
Songqing
S
Galbreath
Elizabeth
E
Zhang
Tonghai
T
Yang
Derek D
DD
Glasebrook
Andrew
A
Song
Ho Yeong
HY
D000208:Acute Disease; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
D007519:Isoantigens; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse