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Blood, 15 July 2006, Vol. 108, No. 2, pp. 409-410.
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IMMUNOBIOLOGY
Comment on Cornish et al, page 600
Time to restore individual rights for IL-2 and IL-15?
Yutaka Tagaya
NATIONAL CANCER INSTITUTE
IL-2 and IL-15 transduce distinct signals in the same cell despite their sharing of all signaling receptor components.
The immune system uses many cytokines to accomplish diverse functions. It is sometimes amazing that the system can avoid confusion, especially given that many cytokines share receptor and signaling components. While most cytokines share only part of the signaling receptor components, the case of interleukin (IL)–2 and IL-15 seems unique because they share all the signaling receptor components (ie, CD122 and CD132). Each of these cytokines requires a private  chain (CD25 and IL-15R) for stable binding to the CD122/132 complexes in vivo, and these chains have different cellular distribution, which may explain why IL-2–/– and IL-15–/– mice have totally different phenotypes. Thus, the question of whether IL-2 and IL-15 transduce distinct signals at a single-cell level has been controversial. Ku et al1 demonstrated that IL-2 and IL-15 display contrasting effects on the survival of memory-phenotype CD8 T cells, which could indicate signaling differences between these two cytokines. However, the basal interpretation of this study has been challenged recently by Boyman et al,2 who discovered that the anti–IL-2 antibody used in the original study bound IL-2 in vivo but converted it into a "superagonist" by forming stable IL-2/anti–IL-2 complexes, rather than neutralizing the effect of IL-2. Such superagonistic IL-2 can expand memory phenotype CD8 T cells even in IL-15–/– mice; thus, the action of these complexes seems similar to that of IL-15 in this context.2 So do these 2 factors have distinct in vivo functions only because they act on different target cells? It has been suggested that IL-15R transduces its own signal upon binding by IL-15, but the process does not seem to operate in vivo, because IL-15–/– and IL-15R–/– mice did not manifest any defects that are not seen with the CD122–/– mice. Moreover, Kovanen et al3 demonstrated that IL-2 and IL-15 (and IL-7) induce very similar gene activation profile using cDNA microarrays, basically suggesting that the IL-2/IL-15 receptors do not distinguish these 2 cytokines functionally at a single-cell level.
In this issue of Blood, Cornish and colleagues present elegant and interesting insights into this question. They demonstrated that IL-15 primarily activates proliferation (and thus acts as a mitogen), whereas IL-2 activates more diverse pathways including proliferation, amino acid uptake, and protein synthesis (hence, IL-2 is a genuine growth factor) in ex vivo CD8 T cells. IL-2–cultured and IL-15–cultured CD8 T cells consistently exhibited distinct morphology and expressed different cell-surface antigens. They also demonstrated that such differences might arise from differential kinetics of the signaling through the Akt (PKB)–PDK1 pathway (see figure). These observations do not seem to contradict the earlier microarray study,3 because the difference in the signaling kinetics may be translated into cellular events at later points that the microarray analyses did not cover. While the mechanism underlying these observations needs to be investigated, Cornish et al's study undoubtedly sheds new light on how we interpret and design in vivo experiments. In parallel, Dubois et al4 and other groups demonstrated that IL-15 is presented to target cells in trans, which may be the dominant way IL-15 operates in vivo.5 It is reasonable to assume that trans-presented IL-15 may signal very differently from IL-2, since such IL-15 signals inevitably include elements coming from cell-to-cell contact. Finally, IL-15 is being considered as a clinical therapeutic agent as a replacement for IL-2 because of its less-toxic nature, but the current study poses a challenge to this concept and urges us to consider IL-2 and IL-15 as distinct factors. 
References
- Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P. Control of homeostatis of CD8+ memory T cells by opposing cytokines. Science. 2000;28: 675-678.
- Boyman O, Kovar M, Rubinstein R, Surh C, Sprent J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311: 1924-1927.[Abstract/Free Full Text]
- Kovanen PE, Rosenwald A, Fu J, et al. Analysis of
 c-family cytokine target genes: identification of dual-specificity phosphatase 5 (DUSP4) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling. J Biol Chem. 2003;278: 5205-5213.[Abstract/Free Full Text]
- Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15R recycles and presents IL-15 in trans to neighboring cells. Immunity. 2000;17: 537-547.
- Lodolce JP, Burkett PR, Boone DL, Chien M, Ma A. T cell-independent interleukin 15R signals are required for bystander proliferation. J Exp Med. 2001;194: 1187-1194.[Abstract/Free Full Text]
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