Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease.
The role of T helper (Th) 1 and Th2 polarization in acute graft-vs-host-disease (GVHD) is unclear. We investigated the role of Th2 cytokine secretion by utilizing donor T cells that cannot make interleukin (IL)-4, IL-5, IL-9, and IL-13 from quadruple cytokine-deficient (Quad-KO) animals in a well-characterized BALB/c-->C57BL/6 model of allogeneic bone marrow transplantation. B6 recipients of BALB/c Quad-KO T cells demonstrated greater clinical severity, target organ damage, and mortality from GVHD than recipients of BALB/c wild-type (WT) T cells. When compared with donor T cells that are deficient in signal transducers and activators of transcription 6 signaling or the signature Th2 cytokine, IL-4, Quad-KO T cells demonstrated greater GVHD mortality. Mechanistic studies demonstrated that Quad-KO T cells demonstrated enhanced T-cell proliferation than WT T cells when stimulated with either allogeneic antigen-presenting cells or with nonspecific stimuli, such as anti-CD3 monoclonal antibody. Quad-KO T cells also secreted greater amounts of Th1 cytokines and IL-17 compared to WT T cells. Deficiency of Th2 cytokines, however, did not alter the allospecific cytotoxic responses, the numbers of immunoregulatory CD4(+)CD25(+) Foxp3(+) T cells or their suppressive functions. Our data thus unequivocally demonstrate that deficiency of the four classical Th2 cytokine enhances T-cell proliferative responses and aggravates GVHD.
Tawara
Isao
I
Department of Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109 USA.
Maeda
Yoshinobu
Y
Sun
Yaping
Y
Lowler
Kathleen P
KP
Liu
Chen
C
Toubai
Tomomi
T
McKenzie
Andrew N J
AN
Reddy
Pavan
P
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology*; D007159:Immunologic Tests; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007378:Interleukins / Q000172:deficiency* / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology; D014184:Transplantation, Homologous
D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins