Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

Takuya Yamaguchi; Chia Jung Chang; Axel Karger; Markus Keller; Florian Pfaff; Eakapol Wangkahart; Tiehui Wang; Christopher J. Secombes; Azusa Kimoto; Mitsuru Furihata; Keiichiro Hashimoto; Uwe Fischer; Johannes M. Dijkstra

doi:10.3389/fimmu.2020.549319

Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

Takuya Yamaguchi, Chia Jung Chang, Axel Karger, Markus Keller, Florian Pfaff, Eakapol Wangkahart, Tiehui Wang, Christopher J. Secombes, Azusa Kimoto, Mitsuru Furihata, Keiichiro Hashimoto, Uwe Fischer^*, Johannes M. Dijkstra

^*Corresponding author for this work

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

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Abstract

Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4⁻CD8⁻(IgM⁻) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4⁺CD8⁺ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.

Original language	English
Article number	549319
Number of pages	30
Journal	Frontiers in Immunology
Volume	11
DOIs	https://doi.org/10.3389/fimmu.2020.549319
Publication status	Published - 29 Oct 2020

Bibliographical note

Acknowledgments
We thank Mrs. Susann Schares and Katrin Giesow for excellent technical assistance and Dr. Gunther Keil for his valuable advice regarding expression of recombinant proteins in insect cells. We also thank Prof. Oriol Sunyer from the University of Pennsylvania, USA, for providing us mAbs against rainbow trout CD4. A large part of this manuscript has been released as a pre-print (116).

Funding
TY and UF were supported by the EU FP7 Grant 311993 (TARGETFISH) and the German Research Council Grant No. FI 604/7-1. JD was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grants-in-Aid for Scientific Research No. 25450319. TW received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland), that was funded by the Scottish Funding Council (grant reference HR09011). EW was supported by the Ministry of Science and Technology of Thailand and Mahasarakham University.

Keywords

evolution
fish
IL-15
IL-15-like
IL-15Rα
IL-2
type 2 immunity

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Cite this

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title = "Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response",

abstract = "Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4−CD8−(IgM−) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.",

keywords = "evolution, fish, IL-15, IL-15-like, IL-15Rα, IL-2, type 2 immunity",

author = "Takuya Yamaguchi and Chang, {Chia Jung} and Axel Karger and Markus Keller and Florian Pfaff and Eakapol Wangkahart and Tiehui Wang and Secombes, {Christopher J.} and Azusa Kimoto and Mitsuru Furihata and Keiichiro Hashimoto and Uwe Fischer and Dijkstra, {Johannes M.}",

note = "Acknowledgments We thank Mrs. Susann Schares and Katrin Giesow for excellent technical assistance and Dr. Gunther Keil for his valuable advice regarding expression of recombinant proteins in insect cells. We also thank Prof. Oriol Sunyer from the University of Pennsylvania, USA, for providing us mAbs against rainbow trout CD4. A large part of this manuscript has been released as a pre-print (116). Funding TY and UF were supported by the EU FP7 Grant 311993 (TARGETFISH) and the German Research Council Grant No. FI 604/7-1. JD was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grants-in-Aid for Scientific Research No. 25450319. TW received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland), that was funded by the Scottish Funding Council (grant reference HR09011). EW was supported by the Ministry of Science and Technology of Thailand and Mahasarakham University. ",

year = "2020",

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doi = "10.3389/fimmu.2020.549319",

language = "English",

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T1 - Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

AU - Yamaguchi, Takuya

AU - Chang, Chia Jung

AU - Karger, Axel

AU - Keller, Markus

AU - Pfaff, Florian

AU - Wangkahart, Eakapol

AU - Wang, Tiehui

AU - Secombes, Christopher J.

AU - Kimoto, Azusa

AU - Furihata, Mitsuru

AU - Hashimoto, Keiichiro

AU - Fischer, Uwe

AU - Dijkstra, Johannes M.

N1 - Acknowledgments We thank Mrs. Susann Schares and Katrin Giesow for excellent technical assistance and Dr. Gunther Keil for his valuable advice regarding expression of recombinant proteins in insect cells. We also thank Prof. Oriol Sunyer from the University of Pennsylvania, USA, for providing us mAbs against rainbow trout CD4. A large part of this manuscript has been released as a pre-print (116). Funding TY and UF were supported by the EU FP7 Grant 311993 (TARGETFISH) and the German Research Council Grant No. FI 604/7-1. JD was supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grants-in-Aid for Scientific Research No. 25450319. TW received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland), that was funded by the Scottish Funding Council (grant reference HR09011). EW was supported by the Ministry of Science and Technology of Thailand and Mahasarakham University.

PY - 2020/10/29

Y1 - 2020/10/29

N2 - Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4−CD8−(IgM−) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.

AB - Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4−CD8−(IgM−) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.

KW - evolution

KW - fish

KW - IL-15

KW - IL-15-like

KW - IL-15Rα

KW - IL-2

KW - type 2 immunity

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VL - 11

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 549319

ER -

Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

Abstract

Bibliographical note

Keywords

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