title: Interleukin-21 induces proliferation and modulates receptor expression and effector function in canine natural killer cells.
abstract: Interleukin (IL)-21 is an important modulator of natural killer (NK) cell function. However, little is known about IL-21 function in canine NK cells because the phenotype of these cells remains undefined. In this study, we selectively expanded non-B and non-T large granular NK lymphocytes (CD3(-)CD21(-)CD5(-)CD4(-)TCRαβ(-)TCRγδ(-)) ex vivo from the peripheral blood mononuclear cells (PBMCs) of healthy dogs using a combination of IL-2, IL-15, and IL-21 in the presence of 100 Gy-irradiated K562 cells. We investigated the effects of varying the duration and timing of IL-21 treatment on stimulation of proliferation, expression of NK-related receptors, anti-tumor activity and production of interferon (IFN)-γ. The expanded NK cells in each treatment group became enlarged and highly granular after 21 days in culture. NK cells proliferated rapidly in response to activation by IL-21 for 3 weeks, and IL-21 was able to induce changes in the mRNA expression of NK cell-related receptors and enhance the effector function of NK cells in perforin- and granzyme-B-dependent manners. The duration, frequency and timing of IL-21 stimulation during culture affected the rate of proliferation, patterns of receptor expression, cytokine production, and anti-tumor activity. The optimal conditions for maximizing the IL-21-induced proliferation and effector function of NK cells in the presence of IL-2 and IL-15 were seen in cells treated with IL-21 for the first 7 days of culture but without any further IL-21 stimulation other than an additional 2-day treatment prior to harvesting on day 21. The results of this study suggest that synergistic interactions of IL-21 with IL-2 and IL-15 play an important role in the proliferation, receptor expression, and effector function of canine NK cells.
authors.affiliation: Department of Companion & Laboratory Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Shin
authors.affiliation: Department of Companion & Laboratory Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea; Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo 519-809, Republic of Korea.
authors.forename: Soo-Hyeon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Companion & Laboratory Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Companion & Laboratory Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea; Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo 519-809, Republic of Korea.
authors.forename: Ju-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo 519-809, Republic of Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Internal Medicine, Colleage of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Guk-Hyun
authors.initials: GH
authors.lastname: Suh
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo 519-809, Republic of Korea.
authors.forename: Youn-Kyung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo 519-809, Republic of Korea; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Electronic address: hasomii@hanmail.net.
authors.forename: Duck
authors.initials: D
authors.lastname: Cho
authors.affiliation: Department of Companion & Laboratory Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea. Electronic address: sangki@kongju.ac.kr.
authors.forename: Sang-Ki
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D018956:CD5 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay / Q000662:veterinary; D005434:Flow Cytometry / Q000662:veterinary; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology; D007378:Interleukins / Q000494:pharmacology* / Q000502:physiology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D018956:CD5 Antigens; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017464:Receptors, Complement 3d; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: Canine; Effector function; Interleukin-21; NK cells; Proliferation