Abstract
IL-15 is a cytokine of the common γ-chain family that is critical for natural killer (NK), invariant natural killer T (i NKT), and CD8 memory T cell development and homeostasis. The role of IL-15 in regulating effector T cell subsets, however, remains incompletely understood. IL-15 is mostly expressed by stromal cells, myeloid cells, and dendritic cells (DCs). Whether T cells themselves can express IL-15, and if so, whether such T cell-derived IL-15 could play an autocrine role in T cells are interesting questions that were previously addressed but answered with mixed results. Recently, three independent studies described the generation of IL-15 reporter mice which facilitated the identification of IL-15-producing cells and helped to clarify the role of IL-15 both in vitro and in vivo. Here, we review the findings of these studies and place them in context of recent reports that examined T cell-intrinsic IL-15 expression during CD4 effector T cell differentiation.
References
1. Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994; 91:4940–4944.
2. Burton JD, Bamford RN, Peters C, Grant AJ, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994; 91:4935–4939.
3. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994; 13:2822–2830.
4. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994; 264:965–968.
5. Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J. 1995; 14:3654–3663.
6. Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015; 3:219–227.
7. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD, et al. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci U S A. 1995; 92:8705–8709.
8. Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S, et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995; 2:331–339.
9. Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005; 310:1159–1163.
10. Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004; 21:289–302.
11. Waickman AT, Park JY, Park JH. The common gamma-chain cytokine receptor: tricks-and-treats for T cells. Cell Mol Life Sci. 2016; 73:253–269.
12. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol. 2007; 178:2018–2027.
13. Etzensperger R, Kadakia T, Tai X, Alag A, Guinter TI, Egawa T, Erman B, Singer A. Identification of lineage-specifying cytokines that signal all CD8 (+)-cytotoxic-lineage-fate ‘decisions'in the thymus. Nat Immunol. 2017; 18:1218–1227.
14. McCaughtry TM, Etzensperger R, Alag A, Tai X, Kurtulus S, Park JH, Grinberg A, Love P, Feigenbaum L, Erman B, et al. Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med. 2012; 209:2263–2276.
15. Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012; 13:1187–1195.
16. Castro I, Yu A, Dee MJ, Malek TR. The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J Immunol. 2011; 187:5170–5182.
17. Cornish GH, Sinclair LV, Cantrell DA. Differential regulation of T-cell growth by IL-2 and IL-15. Blood. 2006; 108:600–608.
18. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013; 38:13–25.
19. Budagian V, Bulanova E, Paus R, Bulfone-Paus S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev. 2006; 17:259–280.
21. Colpitts SL, Puddington L, Lefrancois L. IL-15 receptor alpha signaling constrains the development of IL-17-producing gammadelta T cells. Proc Natl Acad Sci U S A. 2015; 112:9692–9697.
22. Wu Z, Xue HH, Bernard J, Zeng R, Issakov D, Bollenbacher-Reilley J, Belyakov IM, Oh S, Berzofsky JA, Leonard WJ. The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15Ralpha function but is not required for transpresentation. Blood. 2008; 112:4411–4419.
23. Pandiyan P, Yang XP, Saravanamuthu SS, Zheng L, Ishihara S, O'Shea JJ, Lenardo MJ. The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes. J Immunol. 2012; 189:4237–4246.
24. Colpitts SL, Stonier SW, Stoklasek TA, Root SH, Aguila HL, Schluns KS, Lefrancois L. Transcriptional regulation of IL-15 expression during hematopoiesis. J Immunol. 2013; 191:3017–3024.
25. Waickman AT, Ligons DL, Hwang S, Park JY, Lazarevic V, Sato N, Hong C, Park JH. CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans. Cytokine. 2017; 99:266–274.
26. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000; 191:771–780.
27. Marks-Konczalik J, Dubois S, Losi JM, Sabzevari H, Yamada N, Feigenbaum L, Waldmann TA, Tagaya Y. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A. 2000; 97:11445–11450.
28. Yokohama A, Mishra A, Mitsui T, Becknell B, Johns J, Curphey D, Blaser BW, Vandeusen JB, Mao H, Yu J, et al. A novel mouse model for the aggressive variant of NK cell and T cell large granular lymphocyte leukemia. Leuk Res. 2010; 34:203–209.
29. Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity. 2002; 17:537–547.
30. Stonier SW, Schluns KS. Trans-presentation: a novel mechanism regulating IL-15 delivery and responses. Immunol Lett. 2010; 127:85–92.
31. Burkett PR, Koka R, Chien M, Chai S, Boone DL, Ma A. Coordinate expression and trans presentation of interleukin (IL)-15Ralpha and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. J Exp Med. 2004; 200:825–834.
32. Sandau MM, Schluns KS, Lefrancois L, Jameson SC. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells. J Immunol. 2004; 173:6537–6541.
33. Lin JX, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 2000; 19:2566–2576.
34. Anthony SM, Howard ME, Hailemichael Y, Overwijk WW, Schluns KS. Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways. PLoS One. 2015; 10:e0120274.
35. Nishimura H, Yajima T, Naiki Y, Tsunobuchi H, Umemura M, Itano K, Matsuguchi T, Suzuki M, Ohashi PS, Yoshikai Y. Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo. J Exp Med. 2000; 191:157–170.
36. Anderson DM, Johnson L, Glaccum MB, Copeland NG, Gilbert DJ, Jenkins NA, Valentine V, Kirstein MN, Shapiro DN, Morris SW, et al. Chromosomal assignment and genomic structure of IL15. Genomics. 1995; 25:701–706.
37. Kurys G, Tagaya Y, Bamford R, Hanover JA, Waldmann TA. The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15. J Biol Chem. 2000; 275:30653–30659.
38. Gaggero A, Azzarone B, Andrei C, Mishal Z, Meazza R, Zappia E, Rubartelli A, Ferrini S. Differential intracellular trafficking, secretion and endosomal localization of two IL-15 isoforms. Eur J Immunol. 1999; 29:1265–1274.
39. Colpitts SL, Stoklasek TA, Plumlee CR, Obar JJ, Guo C, Lefrancois L. Cutting edge: the role of IFN-alpha receptor and MyD88 signaling in induction of IL-15 expression in vivo. J Immunol. 2012; 188:2483–2487.
40. Sosinowski T, White JT, Cross EW, Haluszczak C, Marrack P, Gapin L, Kedl RM. CD8alpha+ dendritic cell trans presentation of IL-15 to naive CD8+ T cells produces antigen-inexperienced T cells in the periphery with memory phenotype and function. J Immunol. 2013; 190:1936–1947.
41. Donnelly ML, Hughes LE, Luke G, Mendoza H, ten Dam E, Gani D, Ryan MD. The ‘cleavage'activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring ‘2A-like'sequences. J Gen Virol. 2001; 82:1027–1041.
42. Donnelly ML, Luke G, Mehrotra A, Li X, Hughes LE, Gani D, Ryan MD. Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage'mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip'. J Gen Virol. 2001; 82:1013–1025.
43. Ryan MD, King AM, Thomas GP. Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol. 1991; 72:2727–2732.
44. Cui G, Hara T, Simmons S, Wagatsuma K, Abe A, Miyachi H, Kitano S, Ishii M, Tani-ichi S, Ikuta K. Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. Proc Natl Acad Sci U S A. 2014; 111:1915–1920.
45. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006; 25:977–988.
46. Bendelac A, Rivera MN, Park SH, Roark JH. Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu Rev Immunol. 1997; 15:535–562.
47. Gordy LE, Bezbradica JS, Flyak AI, Spencer CT, Dunkle A, Sun J, Stanic AK, Boothby MR, He YW, Zhao Z, et al. IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol. 2011; 187:6335–6345.
48. Park JY, Jo Y, Ko E, Luckey MA, Park YK, Park SH, Park JH, Hong C. Soluble gammac cytokine receptor suppresses IL-15 signaling and impairs i NKT cell development in the thymus. Sci Rep. 2016; 6:36962.
49. Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS. Thymic and peripheral microenvironments differentially mediate development and maturation of i NKT cells by IL-15 transpresentation. Blood. 2010; 116:2494–2503.
50. Vallabhapurapu S, Powolny-Budnicka I, Riemann M, Schmid RM, Paxian S, Pfeffer K, Korner H, Weih F. Rel/NF-kappaB family member RelA regulates NK1.1- to NK1.1+ transition as well as IL-15-induced expansion of NKT cells. Eur J Immunol. 2008; 38:3508–3519.
51. White AJ, Jenkinson WE, Cowan JE, Parnell SM, Bacon A, Jones ND, Jenkinson EJ, Anderson G. An essential role for medullary thymic epithelial cells during the intrathymic development of invariant NKT cells. J Immunol. 2014; 192:2659–2666.
52. Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity. 1998; 9:669–676.
53. Suzuki H, Duncan GS, Takimoto H, Mak TW. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J Exp Med. 1997; 185:499–505.
54. Lai YG, Hou MS, Hsu YW, Chang CL, Liou YH, Tsai MH, Lee F, Liao NS. IL-15 does not affect IEL development in the thymus but regulates homeostasis of putative precursors and mature CD8αα+ IELs in the intestine. J Immunol. 2008; 180:3757–3765.
55. Ma LJ, Acero LF, Zal T, Schluns KS. Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8alphaalpha IELs. J Immunol. 2009; 183:1044–1054.
56. Meijssen MA, Brandwein SL, Reinecker HC, Bhan AK, Podolsky DK. Alteration of gene expression by intestinal epithelial cells precedes colitis in interleukin-2-deficient mice. Am J Physiol. 1998; 274:G472–G479.
57. Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK. Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology. 1996; 111:1706–1713.
58. Schluns KS, Nowak EC, Cabrera-Hernandez A, Puddington L, Lefrancois L, Aguila HL. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc Natl Acad Sci U S A. 2004; 101:5616–5621.
59. Ohta N, Hiroi T, Kweon MN, Kinoshita N, Jang MH, Mashimo T, Miyazaki J, Kiyono H. IL-15-dependent activation-induced cell death-resistant Th1 type CD8 alpha beta+NK1.1+ T cells for the development of small intestinal inflammation. J Immunol. 2002; 169:460–468.
60. Musso T, Calosso L, Zucca M, Millesimo M, Ravarino D, Giovarelli M, Malavasi F, Ponzi AN, Paus R, Bulfone-Paus S. Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15. Blood. 1999; 93:3531–3539.
61. Neely GG, Robbins SM, Amankwah EK, Epelman S, Wong H, Spurrell JC, Jandu KK, Zhu W, Fogg DK, Brown CB, et al. Lipopolysaccharide-stimulated or granulocyte-macrophage colony-stimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis. J Immunol. 2001; 167:5011–5017.
62. Mortier E, Advincula R, Kim L, Chmura S, Barrera J, Reizis B, Malynn BA, Ma A. Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets. Immunity. 2009; 31:811–822.
63. Castillo EF, Stonier SW, Frasca L, Schluns KS. Dendritic cells support the in vivo development and maintenance of NK cells via IL-15 transpresentation. J Immunol. 2009; 183:4948–4956.
64. Stonier SW, Ma LJ, Castillo EF, Schluns KS. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation. Blood. 2008; 112:4546–4554.
65. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013; 31:563–604.
66. Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014; 40:642–656.
67. Mattei F, Schiavoni G, Belardelli F, Tough DF. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol. 2001; 167:1179–1187.
68. Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H, Kunzendorf U. Interleukin-15 protects from lethal apoptosis in vivo. Nat Med. 1997; 3:1124–1128.
69. Saligrama PT, Fortner KA, Secinaro MA, Collins CC, Russell JQ, Budd RC. IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3. Cell Death Differ. 2014; 21:904–914.
70. Sato N, Sabzevari H, Fu S, Ju W, Petrus MN, Bamford RN, Waldmann TA, Tagaya Y. Development of an IL-15-autocrine CD8 T-cell leukemia in IL-15-transgenic mice requires the cis expression of IL-15Ralpha. Blood. 2011; 117:4032–4040.
72. Azimi N, Brown K, Bamford RN, Tagaya Y, Siebenlist U, Waldmann TA. Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. Proc Natl Acad Sci U S A. 1998; 95:2452–2457.
73. Miranda-Carús ME, Benito-Miguel M, Llamas MA, Balsa A, Martín-Mola E. Human T cells constitutively express IL-15 that promotes ex vivo T cell homeostatic proliferation through autocrine/juxtacrine loops. J Immunol. 2005; 175:3656–3662.
74. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007; 26:371–381.
75. Anthony SM, Rivas SC, Colpitts SL, Howard ME, Stonier SW, Schluns KS. Inflammatory signals regulate IL-15 in response to lymphodepletion. J Immunol. 2016; 196:4544–4552.