IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation.
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-versus-host 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 gamma (IFNgamma) 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.
Bucher
Christoph
C
University of Minnesota Cancer Center and Department of Pediatrics, Division of BMT, Minneapolis, MN, USA.
Koch
Lisa
L
Vogtenhuber
Christine
C
Goren
Emily
E
Munger
Meghan
M
Panoskaltsis-Mortari
Angela
A
Sivakumar
Pallavur
P
Blazar
Bruce R
BR
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21