4-1BB triggers IL-13 production from T cells to limit the polarized, Th1-mediated inflammation

J Leukoc Biol. 2007 Jun;81(6):1455-65. doi: 10.1189/jlb.1006619. Epub 2007 Mar 27.


4-1BB (CD137) triggering typically induces Th1 response by increasing IFN-gamma from T cells upon TCR ligation. We found recently that 4-1BB costimulation increased the expression of IL-13 from CD4(+) T cells, as well as CD8(+) T cells. The enhanced IL-13 expression by agonistic anti-4-1BB treatment was mediated via MAPK1/2, PI-3K, JNK, mammalian target of rapamycin, NF-AT, and NF-kappaB signaling pathways. The signaling for IL-13 induction was similar to that of IFN-gamma production by anti-4-1BB treatment in T cells. When the anti-4-1BB-mediated IL-13 expression was tested in an in vivo viral infection model such as HSV-1 and vesicular stomatitis virus, 4-1BB stimulation enhanced IL-13 expression of CD4(+) T, rather than CD8(+) T cells. Although IL-13 was enhanced by anti-4-1BB treatment, the increased IL-13 did not significantly alter the anti-4-1BB-induced Th1 polarization of T cells--increase of T-bet and decrease of GATA-3. Nevertheless, anti-4-1BB treatment polarized T cells excessively in the absence of IL-13 and even became detrimental to the mice by causing liver inflammation. Therefore, we concluded that IL-13 was coinduced following 4-1BB triggering to maintain the Th1/2 balance of immune response.

Publication types

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

MeSH terms

  • 4-1BB Ligand / antagonists & inhibitors
  • 4-1BB Ligand / immunology*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Polarity
  • Female
  • Hepatitis, Viral, Animal / immunology
  • Herpes Simplex / immunology
  • Herpes Simplex / metabolism
  • Herpesvirus 1, Human / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interferon-gamma / biosynthesis
  • Interleukin-13 / biosynthesis*
  • Interleukin-13 / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • RNA, Messenger / biosynthesis
  • Receptors, Interleukin-13 / immunology
  • Rhabdoviridae Infections / immunology
  • Rhabdoviridae Infections / metabolism
  • Signal Transduction
  • Th1 Cells / immunology*
  • Vesicular stomatitis Indiana virus / metabolism


  • 4-1BB Ligand
  • Antibodies, Monoclonal
  • Interleukin-13
  • RNA, Messenger
  • Receptors, Interleukin-13
  • Interferon-gamma