TY - JOUR
T1 - 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
AU - Vogtenhuber, Christine
AU - Bucher, Christoph
AU - Highfill, Steven L.
AU - Koch, Lisa K.
AU - Goren, Emily
AU - Panoskaltsis-Mortari, Angela
AU - Taylor, Patricia A.
AU - Farrar, Michael A.
AU - Blazar, Bruce R.
PY - 2010/7/22
Y1 - 2010/7/22
N2 - 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-versushost disease (GVHD) capacity versus wildtype (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 upregulation as a means of decreasing GVHD while retaining a graft-versus-leukemia effect.
AB - 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-versushost disease (GVHD) capacity versus wildtype (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 upregulation as a means of decreasing GVHD while retaining a graft-versus-leukemia effect.
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U2 - 10.1182/blood-2009-11-252825
DO - 10.1182/blood-2009-11-252825
M3 - Article
C2 - 20442366
AN - SCOPUS:77955890092
SN - 0006-4971
VL - 116
SP - 466
EP - 474
JO - Blood
JF - Blood
IS - 3
ER -