TY - JOUR
T1 - Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fcγ2a protein blocks delayed-type hypersensitivity
AU - Kim, Yon Su
AU - Maslinski, Wlodzimierz
AU - Zheng, Xin Xiao
AU - Stevens, A. Christopher
AU - Li, Xian Chang
AU - Tesch, Gregory H.
AU - Kelley, Vicki R.
AU - Strom, Terry B.
PY - 1998/6/15
Y1 - 1998/6/15
N2 - Owing to shared receptor components, the biologic activities of IL-15 are similar to those of IL-2. However, the patterns of tissue expression of IL-2/IL-2Rα and IL-15/IL-15Rα differ. The development of agents targeting the receptor and signaling elements of IL-15 may provide a new perspective for treatment of diseases associated with expression of IL-15/IL-15R. We designed, genetically constructed, and expressed a receptor site-specific IL- 15 antagonist by mutating glutamine residues within the C terminus of IL-15 to aspartic acid and genetically linked this mutant IL-15 to murine Fcγ2a. These mutant IL-15 proteins specifically bind to the IL-15R, competitively inhibit IL-15-triggered cell proliferation, and do not activate the STAT- signaling pathway. Because the receptor site-specific antagonist IL-15 mutant/Fcγ2a fusion proteins had a prolonged t 1/4 in vivo and the potential for destruction of IL-15R+ leukocytes, we examined the immunosuppressive activity of this agent. An IL-15 mutant/Fcγ2a fusion protein markedly attenuated Ag-specific delayed-type hypersensitivity responses and decreased leukocyte infiltration within the delayed-type hypersensitivity sites. These findings suggest that 1) IL-15/IL-15R+ cells are crucial to these T cell- dependent immune responses, and 2) treatment with IL-15 mutant/Fcγ2a protein may ameliorate T cell-dependent immune/inflammatory diseases.
AB - Owing to shared receptor components, the biologic activities of IL-15 are similar to those of IL-2. However, the patterns of tissue expression of IL-2/IL-2Rα and IL-15/IL-15Rα differ. The development of agents targeting the receptor and signaling elements of IL-15 may provide a new perspective for treatment of diseases associated with expression of IL-15/IL-15R. We designed, genetically constructed, and expressed a receptor site-specific IL- 15 antagonist by mutating glutamine residues within the C terminus of IL-15 to aspartic acid and genetically linked this mutant IL-15 to murine Fcγ2a. These mutant IL-15 proteins specifically bind to the IL-15R, competitively inhibit IL-15-triggered cell proliferation, and do not activate the STAT- signaling pathway. Because the receptor site-specific antagonist IL-15 mutant/Fcγ2a fusion proteins had a prolonged t 1/4 in vivo and the potential for destruction of IL-15R+ leukocytes, we examined the immunosuppressive activity of this agent. An IL-15 mutant/Fcγ2a fusion protein markedly attenuated Ag-specific delayed-type hypersensitivity responses and decreased leukocyte infiltration within the delayed-type hypersensitivity sites. These findings suggest that 1) IL-15/IL-15R+ cells are crucial to these T cell- dependent immune responses, and 2) treatment with IL-15 mutant/Fcγ2a protein may ameliorate T cell-dependent immune/inflammatory diseases.
UR - http://www.scopus.com/inward/record.url?scp=0343183719&partnerID=8YFLogxK
M3 - Article
C2 - 9637483
AN - SCOPUS:0343183719
SN - 0022-1767
VL - 160
SP - 5742
EP - 5748
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -