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4-1BB Functions As a Survival Factor in Dendritic Cells¹

Beom K. Choi^*, Young H. Kim^*, Patrick M. Kwon^*, Sang C. Lee, Sang W. Kang, Moon S. Kim^*, Myoung J. Lee^* and Byoung S. Kwon^2,*,,

^* Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Korea; The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea; and Louisiana State University Eye Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112

4-1BB (CD137) is expressed on dendritic cells (DCs) and its biological function has remained largely unresolved. By comparing 4-1BB-intact (4-1BB^+/+) and 4-1BB-deficient (4-1BB^–/–) DCs, we found that 4-1BB was strongly induced on DCs during the maturation and that DC maturation was normal in the absence of 4-1BB. However, DC survival rate was low in the absence of 4-1BB, which was due to the decreased Bcl-2 and Bcl-x_L in 4-1BB^–/– DCs compared with 4-1BB^+/+ DCs after DC maturation. Consistent with these results, 4-1BB^–/– DCs showed an increased turnover rate in steady state and more severely decreased in spleen by injecting LPS compared with 4-1BB^+/+ DCs. When OVA-pulsed DCs were adoptively transferred to recipient mice along with OVA-specific CD4⁺ T cells, 4-1BB^–/– DCs did not properly migrate to the T cell zone in lymph nodes and poorly induced proliferation of CD4⁺ T cells, although both DCs comparably expressed functional CCR7. Eventually, 4-1BB^–/– DCs generated a reduced number of OVA-specific memory CD4⁺ T cells compared with 4-1BB^+/+ DCs. To further assess the role of 4-1BB on DC longevity in vivo, 4-1BB^+/+ and 4-1BB^–/– C57BL/6 were administrated with Propionibacterium acnes that develop liver granuloma by recruiting DCs. Number and size of granuloma were reduced in the absence of 4-1BB, but the inflammatory cytokine level was comparable between the mice, which implied that the granuloma might be reduced due to the decreased longevity of DCs. These results demonstrate that 4-1BB on DCs controls the duration, DC-T interaction, and, therefore, immunogenicity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Cancer Center, Korea (NCC-0810720-2 and NCC-D890830-2) Korean Research Foundation (KRF-2005-201-E00008 and KRF-2005-084-E00001); Korean Science and Engineering Foundation (Stem Cell-M10641000040 and Discovery of Global New Drug-M10870060009); Korea Health 21 R&D (A050260); the Arthritis Foundation (Innovative Research Award to B.S.K.); and National Institutes of Health (R01EY013325 to B.S.K.).

² Address correspondence and reprint requests to Dr. Byoung S. Kwon, Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, 809 Madu, Ilsan, Goyang, Kyounggi-do, Korea 411-769. E-mail address: bskwon{at}ncc.re.kr

³ Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; PLN, popliteal LN; Tg, transgenic; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PI, postinjection; CR, cortical ridge; PCC, paracortical cord; DLN, draining LN; CBA, cytometric bead array; MHC I/II, MHC class I/class II.