Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

Aaron M. Ring; Jian Xin Lin; Dan Feng; Suman Mitra; Mathias Rickert; Gregory R. Bowman; Vijay S. Pande; Peng Li; Ignacio Moraga; Rosanne Spolski; Engin Özkan; Warren J. Leonard; K. Christopher Garcia

doi:10.1038/ni.2449

Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

Aaron M. Ring
, Jian Xin Lin
, Dan Feng
, Suman Mitra
, Mathias Rickert
, Gregory R. Bowman
, Vijay S. Pande
, Peng Li
, Ignacio Moraga
, Rosanne Spolski
, Engin Özkan
, Warren J. Leonard
, K. Christopher Garcia

Research output: Contribution to journal › Article › peer-review

195 Scopus citations

Abstract

Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ c complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ c dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.

Original language	English
Pages (from-to)	1187-1195
Number of pages	9
Journal	Nature immunology
Volume	13
Issue number	12
DOIs	https://doi.org/10.1038/ni.2449
State	Published - Dec 2012

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@article{fbda115b986d47eca085d953c191df25,

title = "Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15",

abstract = "Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ c complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ c dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.",

author = "Ring, \{Aaron M.\} and Lin, \{Jian Xin\} and Dan Feng and Suman Mitra and Mathias Rickert and Bowman, \{Gregory R.\} and Pande, \{Vijay S.\} and Peng Li and Ignacio Moraga and Rosanne Spolski and Engin {\"O}zkan and Leonard, \{Warren J.\} and \{Christopher Garcia\}, K.",

note = "Funding Information: We thank E. Long, M. Rubinstein and members of the Leonard and Garcia laboratories for advice and discussions; and N. Goriatcheva, D. Waghray and S. Fischer for technical assistance. Supported by the US National Institutes of Health (R01 AI51321 to K.C.G.; R01 GM062868 to V.S.P.; and National Research Service Award NIH-F30DK094541 to A.M.R.), the American Recovery and Reinvestment Act of 2009 (Public Law 111-5; MRI-R2 to V.S.P.), the Division of Intramural Research of the National Heart, Lung and Blood Institute (US National Institutes of Health; W.J.L., J.-X.L., P.L., S.M. and R.S.), the Stanford Medical Scientist Training Program (NIH-GM07365 to A.M.R.) and the Howard Hughes Medical Institute (K.C.G.).",

year = "2012",

month = dec,

doi = "10.1038/ni.2449",

language = "English",

volume = "13",

pages = "1187--1195",

journal = "Nature immunology",

issn = "1529-2908",

number = "12",

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T1 - Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

AU - Ring, Aaron M.

AU - Lin, Jian Xin

AU - Feng, Dan

AU - Mitra, Suman

AU - Rickert, Mathias

AU - Bowman, Gregory R.

AU - Pande, Vijay S.

AU - Li, Peng

AU - Moraga, Ignacio

AU - Spolski, Rosanne

AU - Özkan, Engin

AU - Leonard, Warren J.

AU - Christopher Garcia, K.

N1 - Funding Information: We thank E. Long, M. Rubinstein and members of the Leonard and Garcia laboratories for advice and discussions; and N. Goriatcheva, D. Waghray and S. Fischer for technical assistance. Supported by the US National Institutes of Health (R01 AI51321 to K.C.G.; R01 GM062868 to V.S.P.; and National Research Service Award NIH-F30DK094541 to A.M.R.), the American Recovery and Reinvestment Act of 2009 (Public Law 111-5; MRI-R2 to V.S.P.), the Division of Intramural Research of the National Heart, Lung and Blood Institute (US National Institutes of Health; W.J.L., J.-X.L., P.L., S.M. and R.S.), the Stanford Medical Scientist Training Program (NIH-GM07365 to A.M.R.) and the Howard Hughes Medical Institute (K.C.G.).

PY - 2012/12

Y1 - 2012/12

N2 - Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ c complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ c dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.

AB - Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ c complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ c dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.

UR - https://www.scopus.com/pages/publications/84869410452

U2 - 10.1038/ni.2449

DO - 10.1038/ni.2449

M3 - Article

C2 - 23104097

AN - SCOPUS:84869410452

SN - 1529-2908

VL - 13

SP - 1187

EP - 1195

JO - Nature immunology

JF - Nature immunology

IS - 12

ER -

Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

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