Donor B cells in transplants augment clonal expansion and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-host disease.
We reported that both donor CD4(+) T and B cells in transplants were required for induction of an autoimmune-like chronic graft-versus-host disease (cGVHD) in a murine model of DBA/2 donor to BALB/c recipient, but mechanisms whereby donor B cells augment cGVHD pathogenesis remain unknown. In this study, we report that, although donor B cells have little impact on acute GVHD severity, they play an important role in augmenting the persistence of tissue damage in the acute and chronic GVHD overlapping target organs (i.e., skin and lung); they also markedly augment damage in a prototypical cGVHD target organ, the salivary gland. During cGVHD pathogenesis, donor B cells are activated by donor CD4(+) T cells to upregulate MHC II and costimulatory molecules. Acting as efficient APCs, donor B cells augment donor CD4(+) T clonal expansion, autoreactivity, IL-7Rα expression, and survival. These qualitative changes markedly augment donor CD4(+) T cells' capacity in mediating autoimmune-like cGVHD, so that they mediate disease in the absence of donor B cells in secondary recipients. Therefore, a major mechanism whereby donor B cells augment cGVHD is through augmenting the clonal expansion, differentiation, and survival of pathogenic CD4(+) T cells.
Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
James S
JS
Young
Tao
T
Wu
Yuhong
Y
Chen
Dongchang
D
Zhao
Hongjun
H
Liu
Tangsheng
T
Yi
Heather
H
Johnston
Jeremy
J
Racine
Xiaofan
X
Li
Audrey
A
Wang
Ivan
I
Todorov
Defu
D
Zeng
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D002999:Clone Cells; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies