title: IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy.
abstract: IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8(+) T cells, but their distinct effects on antigen-driven differentiation of naive CD8(+) T cells into effector CD8(+) T cells are not clearly understood. We found that antigen-induced expression of Eomesodermin (Eomes) and maturation of naive CD8(+) T cells into granzyme B- and CD44-expressing effector CD8(+) T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8(+) T-cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2 impaired the subsequent antitumor function of transferred cells. Gene expression studies revealed a distinct IL-21 program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced antitumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8(+) T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies.
authors.affiliation: National Cancer Institute, Surgery Branch, National Institutes of Health, Bethesda, MD 20892-1502, USA. christian_hinrichs@nih.gov
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kerstann
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D005434:Flow Cytometry; D015870:Gene Expression; D053804:Granzymes / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D018960:Hyaluronan Receptors; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D053804:Granzymes; D000098546:Interleukin-21