Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses.
Overexpression of a constitutively active form of Stat5b (Stat5b-CA) increases regulatory T cells (Tregs). We show that Stat5b-CA transgenic (TG) CD4(+) T cells had a markedly reduced graft-versus-host disease (GVHD) capacity versus wild-type (WT) T cells. Stat5b-CA TG versus WT CD4(+) T cells had a higher proportion of Tregs, which were superior in suppressing alloresponses mediated by CD4(+)CD25(-) effector T cells (Teffs). By day 5 after transplantation, Stat5b-CA TG Tregs had expanded approximately 3-fold more than WT Tregs. Purified Stat5b-CA TG Tregs added to WT CD4(+)CD25(-) Teffs were superior on a per-cell basis for inhibiting GVHD versus WT Tregs. Surprisingly, rigorously Treg-depleted Stat5b-CA TG versus WT CD4(+)CD25(-) Teffs caused less GVHD lethality associated with diminished Teff proinflammatory and increased Th2 anti-inflammatory cytokine responses. Reduced GVHD by Stat5b-CA TG versus WT Teffs could not be explained by conversion into Tregs in day 10 posttransplantation spleen or small intestine. In addition, Stat5b-CA TG Teffs retained a graft-versus-leukemia response. These results indicate a major role for Stat5 in Treg expansion and potency along with a lesser but significant role in Teff activation and suggest a strategy of pharmacologic Stat5b up-regulation as a means of decreasing GVHD while retaining a graft-versus-leukemia effect.
Vogtenhuber
Christine
C
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis 55455, USA.
Bucher
Christoph
C
Highfill
Steven L
SL
Koch
Lisa K
LK
Goren
Emily
E
Panoskaltsis-Mortari
Angela
A
Taylor
Patricia A
PA
Farrar
Michael A
MA
Blazar
Bruce R
BR
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse