Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayed-type hypersensitivity.
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-2R alpha and IL-15/IL-15R alpha 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 Fc gamma2a. 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/Fc gamma2a fusion proteins had a prolonged t(1/2) in vivo and the potential for destruction of IL-15R+ leukocytes, we examined the immunosuppressive activity of this agent. An IL-15 mutant/Fc gamma2a 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/Fc gamma2a protein may ameliorate T cell-dependent immune/inflammatory diseases.
Kim
Y S
YS
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02215, USA.
Maslinski
W
W
Zheng
X X
XX
Stevens
A C
AC
Li
X C
XC
Tesch
G H
GH
Kelley
V R
VR
Strom
T B
TB
D000818:Animals; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008894:Milk Proteins; D010766:Phosphorylation; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D008894:Milk Proteins; D017452:Receptors, IgG; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine