4-1BB triggers IL-13 production from T cells to limit the polarized, Th1-mediated inflammation.
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.
Shin
Su M
SM
The Immunomodulation Research Center, University of Ulsan, San29, Mukeo-Dong, Nam-Ku, Ulsan, Korea 680-749.
Kim
Young H
YH
Choi
Beom K
BK
Kwon
Patrick M
PM
Lee
Hyeon-Woo
HW
Kwon
Byoung S
BS
D053330:4-1BB Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016764:Cell Polarity; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000276:immunology; D006561:Herpes Simplex / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D053660:Receptors, Interleukin-13 / Q000276:immunology; D018353:Rhabdoviridae Infections / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000378:metabolism
D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D018793:Interleukin-13; D012333:RNA, Messenger; D053660:Receptors, Interleukin-13; D007371:Interferon-gamma