Journal
JOURNAL OF IMMUNOLOGY
Volume 187, Issue 3, Pages 1120-1128Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002681
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Funding
- National Cancer Center (Korea) [NCC-0810720-1, NCCF-0890301-1]
- Ministry of Education, Science, and Technology [MEST-2006-04212]
- Korea Health 21 Research and Development Grant [A050260]
- Arthritis Foundation
- Korea Research Foundation [KRF-2005-084-E00001]
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Agonistic anti-4-1BB Ab is known to ameliorate experimental autoimmune encephalomyelitis. 4-1BB triggering typically leads to the expansion of CD8(+) T cells, which produce abundant IFN-gamma, and this in turn results in IDO-dependent suppression of autoimmune responses. However, because neutralization of IFN-gamma or depletion of CD8(+) T cell only partially abrogates the effect of 4-1BB triggering, we sought to identify an additional mechanism of 4-1BB-triggered suppression of autoimmune responses using IFN-gamma-or IFN-gamma R-deficient mice. 4-1BB triggering inhibited the generation of Th17 cells that is responsible for experimental autoimmune encephalomyelitis induction and progression, and increased Foxp3(+)CD4(+) regulatory T (Treg) cells, particularly among CD4(+) T cells. This was not due to a direct effect of 4-1BB signaling on CD4(+) T cell differentiation: 4-1BB signaling not only reduced Th17 cells and increased Treg cells in wild-type mice, which could be due to IFN-g production by the CD8(+) T cells, but also did so in IFN-gamma-deficient mice, in that case by downregulating IL-6 production. These results show that although secondary suppressive mechanisms evoked by 4-1BB triggering are usually masked by the strong effects of IFN-gamma, 4-1BB signaling seems to modulate autoimmune responses by a number of mechanisms, and modulation of the Th17 versus Treg cell balance is one of those mechanisms. The Journal of Immunology, 2011, 187: 1120-1128.
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