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Published online before print March 27, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1006619

Received for publication October 8, 2006.
Revised January 25, 2007.
Accepted for publication February 27, 2007.

Article

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

Su M. Shin ^*, Young H. Kim ^*, Beom K. Choi ^*, Patrick M. Kwon ^*, Hyeon-Woo Lee , and Byoung S. Kwon ^*@

*The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea; Department of Pharmacology, School of Dentistry, Kyung Hee University, Seoul, Korea; and LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA

^@ To whom correspondence should be addressed. E-mail: bskwon{at}mail.ulsan.ac.kr.

	Abstract

4-1BB (CD137) triggering typically induces Th1 response by increasing IFN- 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-B signaling pathways. The signaling for IL-13 induction was similar to that of IFN- 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.

Key Words: costimulation • CD8⁺ T • CD4⁺ T • cytokine