Abstract
Interleukin (IL)-21 is a new member of the type I cytokine superfamily. Although it is most homologous to IL-15, it has a unique receptor chain, IL-21R, that pairs with the γ-common cytokine receptor chain. The first experiments examining the biology of the IL-21 pathway reveal that it is a cytokine with effects on natural killer (NK) cells, T cells, and B cells. Mice deficient in the IL-21 R have also been made, and are being examined for the effects of the IL-21/IL-21R pathway in vivo. Here we summarize our current knowledge of this new cytokine pathway, and its role in innate and adaptive immunity.
Similar content being viewed by others
References
Bazan JF: Structural design and mole cular evolution of acytokine receptor superfamily. Proc Nat Acad Sci USA 1990;87:6934–6938.
Kasaian MT, Whitters MJ, Carter LL Lowe LD, Jussif JM, Deng B, et al.: IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 2002;16:559–569.
Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al.: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000;408:57–63.
Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ: Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Nat Acad Sci USA 2000;97:11439–11444.
Leonard WJ, O'Shea JJ: Jaks and STATs: biological implications. Ann Rev Immunol 1998;16:293–322.
Parrish-Novak J, Foster DC, Holly RD, Clegg CH: Interleukin-21 and the IL-21 receptor novel effectors of NK and T cell responses. J Leukocyte Biol 2002;72: 856–863.
Anderson DM, Johnson L, Glaccum MB, Copeland NG, Gilbert DJ, Jenkins NA, et al.: Chromosomal assignment and genomic structure of IL15. Genomics 1995;25: 701–706.
Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ: Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically, inhibits the differentiation of naive Th cells into interferon gamma-producing Thl cells. J Exp Med 2002;196: 969–977.
Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA: IL-15: a pleiotropic cytokine with diverse recptor/signaling pathways whose expression is controlled at multiple levels. Immunity 1996;4:329–336.
Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K: cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol 2001;167:1–5.
Habib T, Senadheera S, Weinberg K, Kaushansky K: The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK 3. Biochemistry 2002;41:8725–8731.
Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O: Signaling through the hematopoietic cytokine receptors. Ann Rev Immunol 1995;13:369–398.
Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S: IL-21 Up-re gulates the expression of genesassociated with innate immunity and Th1 response. J Immunol 2002;169:3600–3605.
Brenne AT, Baade Ro T, Waage A, Sundan A, Borset M, Hjorth-Hansen H: Interfleukin-21 is a growth and survival factor for human myeloma cells. Blood 2002;99: 3756–3762.
Suto A, Nakajima H, Hirose K, Suzuki K, Kagami SI, Seto Y, et al: Interleukin-21 prevents antigen-induced IgE production by inhibiting germline C ε transcription of IL-4-stimulated B cells. Blood 2002;100:4565–4573.
Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, et al: Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficientmice. J Exp Med 2000;191:771–780.
Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al.: Acritical role for IL-21 inregulating immuno globulin production. Science 2002;298:1630–1634.
Van Leeuwen EM, Gamadia LE, Baars PA, Remmerswaal EB, Ten Berge IJ, Van Lier RA: Proliferation requirements of cytomegalovirus- specific, effector-type human CD8(+) T cells. J Immunol 2002;169: 5838–5843.
Kuhn R, Rajewsky K, Muller W: Generation and analysis of interleukin-4 deficient mice. Science 1991;254: 707–710.
Ueda C, Akasaka T, Kurata M, Maesako Y, Nishikori M, Ichinohasama R, et al.: The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27;p11), which is recurrently observed in diffuse large B-cell lymphoma. Oncogene 2002:21:368–376.
Bennett F, Luxenberg D, Ling V, Wang I-M, Marquette K, Lowe D, et al.: PD-1 engagement upon TCR activitation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4 and IL-21, but not CD28, IL-7 and IL-15 responses. J. Immunol 2003; 170:711–718.