Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease

Exp Hematol. 2008 Aug;36(8):988-96. doi: 10.1016/j.exphem.2008.02.010. Epub 2008 Apr 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Bone Marrow Transplantation / adverse effects
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Graft vs Host Disease / genetics*
  • Graft vs Host Disease / immunology*
  • Immunologic Tests
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukins / deficiency*
  • Interleukins / genetics*
  • Major Histocompatibility Complex / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Survival Rate
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • Th2 Cells / immunology
  • Transplantation, Homologous


  • Interleukin-2 Receptor alpha Subunit
  • Interleukins