TY - JOUR
T1 - IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation
AU - Bucher, Christoph
AU - Koch, Lisa
AU - Vogtenhuber, Christine
AU - Goren, Emily
AU - Munger, Meghan
AU - Panoskaltsis-Mortari, Angela
AU - Sivakumar, Pallavur
AU - Blazar, Bruce R.
PY - 2009/12/17
Y1 - 2009/12/17
N2 - Interleukin-21 (IL-21) enhances T helper 1 (Th1) and Th17 differentiation while inhibiting the conversion of inducible regulatory T cells (Tregs) from naive T cells. To determine the role of IL-21 in graft-versushost disease (GVHD), anti-IL-21 antibody (Ab) was given to recipients of CD25 -CD4+ or CD4+ and CD8+ T-effectors. IL-21 neutralization attenuated GVHD-related weight loss and prolonged survival. Likewise, a majority of mice receiving IL-21-/- CD25- T-effectors survived long term, whereas those receiving wild-type T cells died. The latter recipients had higher grades of GVHD in the ileum and colon. Surprisingly, disruption of IL-21 signaling did not affect IL-17 production, although colon-infiltrating T-effector cells had decreased interferon γ (IFNγ) and increased IL-4 production. FoxP3+ Tregs were increased in colons of anti-IL-21 Ab-treated recipients of FoxP3- IL-21-/- T cells, indicating Treg conversion. Recipients of FoxP3-deficient T-effectors isolated from chimeras were resistant to the GVHD protective effects of IL-21 blockade. Whereas graft-versus-leukemia (GVL) can occur in the absence of IL-21, loss of both IL-21 and perforin expression abrogated GVL. Together, these data indicate that IL-21 suppresses inducible Treg conversion and further suggest that IL-21 blockade is an attractive strategy to reduce GVHD-induced injury.
AB - Interleukin-21 (IL-21) enhances T helper 1 (Th1) and Th17 differentiation while inhibiting the conversion of inducible regulatory T cells (Tregs) from naive T cells. To determine the role of IL-21 in graft-versushost disease (GVHD), anti-IL-21 antibody (Ab) was given to recipients of CD25 -CD4+ or CD4+ and CD8+ T-effectors. IL-21 neutralization attenuated GVHD-related weight loss and prolonged survival. Likewise, a majority of mice receiving IL-21-/- CD25- T-effectors survived long term, whereas those receiving wild-type T cells died. The latter recipients had higher grades of GVHD in the ileum and colon. Surprisingly, disruption of IL-21 signaling did not affect IL-17 production, although colon-infiltrating T-effector cells had decreased interferon γ (IFNγ) and increased IL-4 production. FoxP3+ Tregs were increased in colons of anti-IL-21 Ab-treated recipients of FoxP3- IL-21-/- T cells, indicating Treg conversion. Recipients of FoxP3-deficient T-effectors isolated from chimeras were resistant to the GVHD protective effects of IL-21 blockade. Whereas graft-versus-leukemia (GVL) can occur in the absence of IL-21, loss of both IL-21 and perforin expression abrogated GVL. Together, these data indicate that IL-21 suppresses inducible Treg conversion and further suggest that IL-21 blockade is an attractive strategy to reduce GVHD-induced injury.
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U2 - 10.1182/blood-2009-05-221135
DO - 10.1182/blood-2009-05-221135
M3 - Article
C2 - 19843883
AN - SCOPUS:73949116753
SN - 0006-4971
VL - 114
SP - 5375
EP - 5384
JO - Blood
JF - Blood
IS - 26
ER -