title: In vivo 4-1BB deficiency in myeloid cells enhances peripheral T cell proliferation by increasing IL-15.
abstract: 4-1BB signals are considered positive regulators of T cell responses against viruses and tumors, but recent studies suggest that they have more complex roles in modulating T cell responses. Although dual roles of 4-1BB signaling in T cell responses have been suggested, the underlying mechanisms are still not fully understood. In this study, we tested whether 4-1BB expression affected T cell responses differently when expressed in myeloid versus lymphoid cells in vivo. By assessing the proliferation of 4-1BB(+/+) and 4-1BB(-/-) T cells in lymphocyte-deficient RAG2(-/-) and RAG2(-/-)4-1BB(-/-) mice, we were able to compare the effects on T cell responses of 4-1BB expression on myeloid versus T cells. Surprisingly, adoptively transferred T cells were more responsive in tumor-bearing RAG2(-/-)4-1BB(-/-) mice than in RAG2(-/-) mice, and this enhanced T cell proliferation was further enhanced if the T cells were 4-1BB deficient. Dendritic cells (DCs) rather than NK or tissue cells were the myeloid lineage cells primarily responsible for the enhanced T cell proliferation. However, individual 4-1BB(-/-) DCs were less effective in T cell priming in vivo than 4-1BB(+/+) DCs; instead, more DCs in the secondary lymphoid organs of RAG2(-/-)4-1BB(-/-) mice appeared to induce the enhanced T cell proliferation by producing and transpresenting more IL-15. Therefore, we conclude that in vivo 4-1BB signaling of myeloid cells negatively regulates peripheral T cell responses by limiting the differentiation of DCs and their accumulation in secondary lymphoid organs.
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.affiliation: Biomedicine Production Branch, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea; and.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Don G
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Sang H
authors.initials: SH
authors.lastname: Park
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea;
authors.forename: Jinsun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112.
authors.forename: Dass S
authors.initials: DS
authors.lastname: Vinay
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea; Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112 bskwon@ncc.re.kr.
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D053330:4-1BB Ligand / Q000172:deficiency / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D019409:Interleukin-15