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CUTTING EDGE |
by the Same Cells1
* Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455; and
Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030
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Abstract |
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chain can bind soluble IL-15 and "transpresent" the cytokine to other cells, allowing the latter to respond to IL-15. However, it is unclear whether IL-15 is normally secreted and then becomes bound to surface IL-15R on bystander cells, or whether transpresentation is mediated by the same cells which synthesize IL-15. Using mixed bone marrow chimeric mice, we present evidence for the latter model, showing that development of NK cells and memory phenotype CD8 T cells necessitates that both IL-15 and IL-15R be expressed by the same population of cells. These data argue that soluble forms of IL-15 are irrelevant for physiological responses to this cytokine, and the implications of this finding are discussed. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, IL-2R
, and common 
-chain (c),4 are involved in reactivity to IL-15. Accordingly, mice deficient in any of the three receptor chains, or in IL-15 itself, exhibit defects in development of the lymphocyte subsets discussed above (1, 2, 3).
Recent reports suggest a unique mechanism of IL-15 recognition. Cells bearing the IL-15R chain, which binds IL-15 with high affinity, can "transpresent" the cytokine to bystander cells expressing the c and IL-2R chains, allowing the latter cells to functionally respond to IL-15 (4). Transpresentation appears to dominate in vivo, in that cells expressing all three components of the IL-15R are unable to be maintained in an environment where bystander cells lack IL-15R, while, conversely, cells lacking the IL-15R chain can develop and be maintained providing bystander cells transpresent IL-15 (5, 6).
A simple model of transpresentation might be that secreted IL-15 in the serum or tissues becomes associated with IL-15R chain on bystander cells, which either respond to IL-15 directly, or transpresent the cytokine to other cells. However, even cells expressing considerable levels of IL-15 mRNA secrete only low levels of IL-15 (7), suggesting free IL-15 may be rare in normal tissues. In contrast, IL-15 and IL-15R mRNA have a broad tissue distribution and some cells, including dendritic cells and activated monocytes, express both proteins (4, 7, 8). Hence, an alternative scenario is that IL-15 transpresentation is mediated by cells which both produce IL-15 and display it bound to their own IL-15R chain.
To test these models of transpresentation, bone marrow chimeras were produced using a mixture of IL-15–/– and IL-15R –/– bone marrow to reconstitute an irradiated host. With conventional cytokine systems, this would lead to complementation of at least one of the bone marrow sources and thus appearance of IL-15-sensitive lymphoid populations. In contrast, however, we show that these chimeras failed to develop or sustain memory CD8 T cells and mature NK cells. These data support a model in which reactivity to IL-15 requires transpresentation by cells which coexpress IL-15 and the IL-15R chain.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6 (B6), B6.SJL, B6.PL, and B6.129 IL-15R –/– mice (The Jackson Laboratory, Bar Harbor, ME) and C57BL/6 IL-15–/– (Taconic Farms, Germantown, NY) were used. In Fig. 4, IL-15–/– and IL-15R –/– animals were >10 generations backcrossed to B6 and were derived from mice provided by J. Peschon (Immunex, Seattle, WA) and A. Ma (University of California, San Francisco, CA), respectively. OT-I TCR transgenic mice (9) were originally obtained from F. Carbone (University of Melbourne, Melbourne, Australia) and W. Heath (Walter and Eliza Hall Institute, Melbourne, Australia). All mice were maintained under specific pathogen-free conditions at the University of Minnesota or at the University of Connecticut Health Center.
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Bone marrow cells from B6.PL (or B6.SJL), IL-15–/–, and IL-15R –/– mice were depleted of T cells by culture, in the presence of complement, with anti-Thy1.2 (30H12) or anti-Thy1.1 (1A14) (for Figs. 1–3), or with anti-Thyl (T24; for Fig. 4). Mixed bone marrows (see Fig. 1) were injected into the tail vain of lethally irradiated (900–1000 cGy) IL-15R–/– mice. Chimeras were used 9–12 wk later for analysis or as recipients for cell transfer.
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To generate memory CD8 T cells, B6 mice were adoptively transferred with OT-I TCR transgenic T cells and infected with vesicular stomatitis virus-OVA >50 days before sacrifice. Spleen cells were magnetically depleted of CD4 T cells and B cells (yielding 
85% CD8 T cell purity), labeled with CFSE and transferred, such that each recipient chimera received 9 x 106 CD8 T cells containing 2.0 x 106 OVA/Kb tetramer+ cells. Chimeras were sacrificed 6 wk later, and splenocytes were analyzed for absolute numbers and CFSE dilution of OVA/Kb tetramer+ cells. The percentage of cells of the original population that had divided (the "responding" population, R) was calculated as described previously (10).
Flow cytometric analysis
Cells were stained with the indicated Abs (BD Pharmingen, San Diego, CA, or eBioscience, San Diego, CA) and analyzed using a FACSCalibur (BD Biosciences, San Jose, CA) and FlowJo software (TreeStar, San Carlos, CA). NK cells were identified as being CD3–, NK1.1+, and (in some experiments) DX5+. In some experiments, dendritic cells were released from the spleen by treatment with 400 U/ml collagenase D (Boehringer Mannheim, Indianapolis, IN) in 10 mM EDTA (Sigma-Aldrich, St. Louis, MO), depleted of RBC, and plated overnight in 48-well plates at 5 x 106 cells/well in RPMI 1640 medium at 37°C to activate dendritic cells. Anti-IL-15R was obtained from R&D Systems (Minneapolis, MN).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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During transpresentation, IL-15 is bound to the IL-15R chain on one cell (here termed a cytokine-presenting cell, or CPC) and is offered to an IL-15-responsive cell which must minimally express IL-2R and c (Fig. 1). The CPC may bind IL-15 secreted by another cell (Fig. 1A, Model 1) or the CPC may both produce the cytokine and transpresent it, in which case the CPC must express both IL-15 and IL-15R (Fig. 1A, Model 2). To test these opposing models, we constructed mixed bone marrow chimeras (Fig. 1B) in which bone marrow-derived cells differed in their capacity to express IL-15 and IL-15R. In control chimeras (groups 1 and 2), congenic wild-type bone marrow was mixed in a 1:1 ratio with either IL-15–/– or IL-15R –/–bone marrow cells. Test chimeras were generated from a 1:1 mixture of IL-15–/– and IL-15R –/– bone marrow (mixed knockout chimeras, group 3 in Fig. 1B). In these chimeras one population could produce IL-15 but could not express the IL-15R chain, while the other hemopoietic population could express the receptor but not the cytokine. Previous work from Schluns et al. (6) demonstrated that both bone marrow and parenchymal cells can contribute to IL-15 transpresentation. To focus on the role of IL-15 transpresentation by bonemarrow-derived cells, we used IL-15R –/– mice as the chimera hosts (Fig. 1B).
We first tested whether both bone marrow donors had contributed to hemopoietic cells. Congenic markers (Thy-1 or CD45 alleles) distinguished donor groups in the control chimeras (groups 1 and 2). Both donors were represented in roughly equal proportions among CD4, CD8, B, and NK cells (e.g., Fig. 1C). To separate the bone marrow donor populations in the mixed knockout chimeras, we tracked expression of IL-15R, which could be detected on cultured CD8 dendritic cells (Fig. 1D) and CD8 T cells (data not shown). By comparisonwith B6 and IL-15R–/–, we could show that group 2 and 3 chimeras possessed both IL-15R+ and IL-15R– cells, suggesting that both bone marrow sources contributed to the hemopoietic pool (Fig. 1D).
Mixed knockout chimeras show deficiency of CD8 memory cells
The different chimeras were compared for reconstitution of B and T cells, with unmanipulated B6 and IL-15R–/– mice serving as a benchmark. B cells and CD4 T cells were found in equivalent percentages across all three chimera groups and were broadly similar in B6 and IL-15R–/– controls (Fig. 2A), in keeping with a lack of IL-15 dependence for these subsets. However, a slight decrease in the percentage of CD8 T cells was found in mixed knockout (group 3) chimeras compared with control chimeras (groups 1 and 2), similar to the lower frequency of CD8 T cells in IL-15R–/– animals. IL-15–/– and IL-15R–/– mice show a striking deficiency of memory phenotype CD8 T cells, which is especially marked for CD8 T cells expressing CD44 and IL-2R (2, 3). Hence, we looked at the frequency of memory phenotype (CD44high) CD8 T cells, of both IL-2R low and IL-2R high subsets, in our chimeras (Fig. 2B). The percentage of cells expressing the memory marker CD44 on CD8 T cells from the control chimeras (groups 1 and 2) was similar to each other and to that of the B6 control (Fig. 2, B and C). However, the percentage of CD44high CD8 T cells in the mixed knockout chimeras was markedly lower than in control chimeras, and this deficit was even more extreme for IL-2RhighCD44highCD8+ T cells (Fig. 2, B and C).
Through IL-15 transpresentation, we would expect IL-15R–/– T cells to contribute to the memory CD8 pool in group 2 chimeras (5, 6). Indeed, by using congenic markers to distinguish donor cells, we could show that IL-15R–/– donor cells contribute to the memory CD8 pool (Fig. 2D). In fact, we note higher frequencies of knockout CD8 memory cells than predicted by overall chimerism in both group 1 and 2 chimeras (Fig. 2D). Although the basis for this is unclear, our data nevertheless reinforce the idea that IL-15 transpresentation rescues IL-15R–/– CD8 memory cells.
In contrast to CD8 cells, both naive (CD45RBhigh) and memory (CD45RBlow) CD4 T cells were found in similar frequencies (Fig. 2, B and E) in all three types of chimera. These data suggest that the mixed knockout chimeras were selectively deficient in generation or maintenance of CD8 memory T cells, while naive CD8 T cells and both naive and memory CD4 T cells was similar between all chimeras.
Similar patterns were observed in all of these experiments if absolute numbers rather than percentage were studied (data not shown).
Mixed knockout chimeras lack mature NK populations
Since NK cells are also IL-15 sensitive (2, 3, 11, 12), we also examined their reconstitution. The percentage of NK cells in bone marrow (Fig. 3A) was lower in all of the chimeras as compared with the B6 control, most likely due to the lack of IL-15R on parenchymal cells in our chimeras (6). However, the mixed knockout chimeras showed a profound decrease (2- to 3-fold) in the percentage of NK cells compared with control chimeras (Fig. 3A). We went on to analyze NK cell maturation in the chimeras. Fully mature NK cells express Mac-1 (M2 integrin), whereas their immediate precursors are Mac-1low (13). Both control chimera groups showed a discrete population of Mac-1high cells in the bone marrow, but this population was virtually absent from the mixed knockout chimeras(Fig. 3B). Immature Mac-1low NK cells were present in mixed knockout chimeras, but their frequency was about one-half that of control chimeras. These defects resemble the pattern for unmanipulated IL-15R –/– animals (Fig. 3). Thus, mixed IL-15–/–/IL-15R –/– bone marrow chimeras failed to develop or maintain mature NK cells. Absolute numbers of bone marrow NK cells were also affected and analogous results were observed in the spleen (data not shown).
Mixed knockout chimeras fail to support homeostasis of Ag-specific memory CD8 T cells
The homeostasis of virus-specific CD8 T cells is due to their basal proliferation in response to IL-15 (14, 15); therefore, we tested whether Ag-specific memory T cells could proliferate in mixed knockout chimeras. CFSE-labeled memory OT-I CD8 T cells were transferred into either group 1 or group 3 chimeric host mice, and their maintenance and proliferation was analyzed 6 wk later (Fig. 4). Memory CD8 T cell proliferation occurred in the control (group 1) chimeras indicated by the loss of CFSE; however, significantly fewer divisions occurred in the mixed knockout (group 3) chimeras (Fig. 4A). Furthermore, greater numbers of memory OT-I T cells persisted in group 1 vs group 3 chimeric hosts (Fig. 4B). Thus, these data reinforce the interpretation that the IL-15–/– plus IL-15Ra–/– mixed chimeras cannot support maintenance of IL-15-dependant cell types.
Overall, our data using mixed knockout chimeras support the model in which a CPC must both express IL-15R and produce IL-15 (Fig. 1A, Model 2). The lack of complementation between the IL-15–/– and IL-15R –/– bone marrow progenitor cells argues that cells cannot utilize secreted IL-15 for transpresentation to IL-15-dependent lymphocytes. A potential caveat with our approach would arise if IL-15 and IL-15R expression is linked, such that deficiency of one protein influences expression of the other. However, previous reports demonstrate normal IL-15 mRNA expression in IL-15R–/– animals (12) and our analysis reveals IL-15R expression on IL-15–/– cells (Fig. 1D), minimizing this concern.
These data suggest IL-15 operates in a radically different manner than most cytokines, which are secreted and can act at a distance from the producing cell. rIL-15 has potent activity in vitro and in vivo (1, 3, 16), and our data do not argue against a potential therapeutic use for soluble IL-15. Rather, we propose endogenous secreted IL-15 is not sufficient for development/maintenance of IL-15-dependent hemopoietic subsets. In this model, IL-15 assumes the properties of a cell surface molecule, in that only the cells that produce the cytokine and the high-affinity receptor will be suitable CPCs. Both dendritic cells and activated monocytes coexpress IL-15 and IL-15R (4, 8), making these cells attractive candidates for hemopoietic IL-15 CPCs.
What consequences does this mode of IL-15 presentation have for IL-15-dependent lymphocytes? If IL-15 is only transpresented by cells that express both IL-15 and IL-15R, this offers a tight regulation of IL-15-dependent cells. For example, although memory CD8 T cells express IL-15R (14) they appear not to produce IL-15. In a simple model of transpresentation, CD8 T cells could both respond to IL-15 and act as CPCs for other CD8 memory cells, leading to unrestrained expansion of the memory CD8 pool. However, in our current model, CPC function is confined to cells which actively synthesize the cytokine, preventing this amplifying loop. These data also reinforce the surprising conclusion that expression of IL-15R may be irrelevant for lymphocyte reactivity to IL-15.
Overall, our data define a novel mechanism by which IL-15 is presented by bone marrow cells to lymphocytes. It will be interesting to determine whether a similar mechanism applies to other cytokines in which one receptor chain carries the majority of the ligand affinity.
Note added in proof.
During review of this manuscript, similar findings were reported by Burkett et al. (Burkett, P. R., R. Koka, M. Chien, S. Chai, D. L. Boone, and A. Ma. 2004. Coordinate expression and trans presentation of interleukin (IL)-15R and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis J. Exp. Med. 200:825.).
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Acknowledgments |
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Footnotes |
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1 This work was supported by National Institutes of Health Grants AI98903 (to S.C.J.) and AI51583 and DK45260 (to L.L.). 
2 Current address: Department of Immunology, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030.
3 Address correspondence and reprint requests to Dr. Stephen C. Jameson, Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, MMC 334, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: james024{at}umn.edu
4 Abbreviations used in this paper: c, common -chain; CPC, cytokine-presenting cell.
Received for publication August 25, 2004. Accepted for publication September 29, 2004.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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recycles and presents IL-15 in trans to neighboring cells. Immunity 17:537.[Medline]
expression on CD8+ T cells is dispensable for T cell memory. Proc. Natl. Acad. Sci. USA 100:4724. expression. Proc. Natl. Acad. Sci. USA 101:5616.-deficient natural killer cells survive in normal but not IL-15R-deficient mice. J. Exp. Med. 197:977.This article has been cited by other articles:
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  J.-s. Do and B. Min IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and {gamma}{delta} T cells in vivo Blood, June 18, 2009; 113(25): 6361 - 6371. [Abstract] [Full Text] [PDF]
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 A. Germeyer, A. M. Sharkey, M. Prasadajudio, R. Sherwin, A. Moffett, K. Bieback, S. Clausmeyer, L. Masters, R. M. Popovici, A. P. Hess, et al. Paracrine effects of uterine leucocytes on gene expression of human uterine stromal fibroblasts Mol. Hum. Reprod., January 1, 2009; 15(1): 39 - 48. [Abstract] [Full Text] [PDF]
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 J. Rowley, A. Monie, C.-F. Hung, and T.-C. Wu Inhibition of Tumor Growth by NK1.1+ Cells and CD8+ T Cells Activated by IL-15 through Receptor {beta}/Common {gamma} Signaling in trans J. Immunol., December 15, 2008; 181(12): 8237 - 8247. [Abstract] [Full Text] [PDF]
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S. W. Stonier, L. J. Ma, E. F. Castillo, and K. S. Schluns Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation Blood, December 1, 2008; 112(12): 4546 - 4554. [Abstract] [Full Text] [PDF]
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 E. Mortier, T. Woo, R. Advincula, S. Gozalo, and A. Ma IL-15R{alpha} chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation J. Exp. Med., May 12, 2008; 205(5): 1213 - 1225. [Abstract] [Full Text] [PDF]
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C.-L. Small, S. McCormick, N. Gill, K. Kugathasan, M. Santosuosso, N. Donaldson, D. E. Heinrichs, A. Ashkar, and Z. Xing NK Cells Play a Critical Protective Role in Host Defense against Acute Extracellular Staphylococcus aureus Bacterial Infection in the Lung J. Immunol., April 15, 2008; 180(8): 5558 - 5568. [Abstract] [Full Text] [PDF]
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A. I. Kokaji, D. L. Hockley, and K. P. Kane IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells J. Immunol., April 1, 2008; 180(7): 4391 - 4401. [Abstract] [Full Text] [PDF]
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Y.-G. Lai, M.-S. Hou, Y.-W. Hsu, C.-L. Chang, Y.-H. Liou, M.-H. Tsai, F. Lee, and N.-S. Liao IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8{alpha}{alpha}+ IELs in the Intestine J. Immunol., March 15, 2008; 180(6): 3757 - 3765. [Abstract] [Full Text] [PDF]
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|
 |
|
 C. Bergamaschi, M. Rosati, R. Jalah, A. Valentin, V. Kulkarni, C. Alicea, G.-M. Zhang, V. Patel, B. K. Felber, and G. N. Pavlakis Intracellular Interaction of Interleukin-15 with Its Receptor {alpha} during Production Leads to Mutual Stabilization and Increased Bioactivity J. Biol. Chem., February 15, 2008; 283(7): 4189 - 4199. [Abstract] [Full Text] [PDF]
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S. Dubois, H. J. Patel, M. Zhang, T. A. Waldmann, and J. R. Muller Preassociation of IL-15 with IL-15R{alpha}-IgG1-Fc Enhances Its Activity on Proliferation of NK and CD8+/CD44high T Cells and Its Antitumor Action J. Immunol., February 15, 2008; 180(4): 2099 - 2106. [Abstract] [Full Text] [PDF]
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|
 |
|
 K. U. Saikh, T. L. Kissner, S. Nystrom, G. Ruthel, and R. G. Ulrich Interleukin-15 Increases Vaccine Efficacy through a Mechanism Linked to Dendritic Cell Maturation and Enhanced Antibody Titers Clin. Vaccine Immunol., January 1, 2008; 15(1): 131 - 137. [Abstract] [Full Text] [PDF]
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S. K. Olsen, N. Ota, S. Kishishita, M. Kukimoto-Niino, K. Murayama, H. Uchiyama, M. Toyama, T. Terada, M. Shirouzu, O. Kanagawa, et al. Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION J. Biol. Chem., December 21, 2007; 282(51): 37191 - 37204. [Abstract] [Full Text] [PDF]
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A. L. Zhang, P. Colmenero, U. Purath, C. Teixeira de Matos, W. Hueber, L. Klareskog, I. H. Tarner, E. G. Engleman, and K. Soderstrom Natural killer cells trigger differentiation of monocytes into dendritic cells Blood, October 1, 2007; 110(7): 2484 - 2493. [Abstract] [Full Text] [PDF]
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M. M. Sandau, C. J. Winstead, and S. C. Jameson IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells J. Immunol., July 1, 2007; 179(1): 120 - 125. [Abstract] [Full Text] [PDF]
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 |
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 N. Sato, H. J. Patel, T. A. Waldmann, and Y. Tagaya The IL-15/IL-15R{alpha} on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells PNAS, January 9, 2007; 104(2): 588 - 593. [Abstract] [Full Text] [PDF]
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|
|
|
|
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X. Zhang, H. Dong, W. Lin, S. Voss, L. Hinkley, M. Westergren, G. Tian, D. Berry, D. Lewellen, R. G. Vile, et al. Human Bone Marrow: A Reservoir for "Enhanced Effector Memory" CD8+ T Cells with Potent Recall Function J. Immunol., November 15, 2006; 177(10): 6730 - 6737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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T. A. Stoklasek, K. S. Schluns, and L. Lefrancois Combined IL-15/IL-15R{alpha} Immunotherapy Maximizes IL-15 Activity In Vivo J. Immunol., November 1, 2006; 177(9): 6072 - 6080. [Abstract] [Full Text] [PDF]
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J. Ritz Trans-presentation of IL-15 Blood, October 1, 2006; 108(7): 2135 - 2136. [Full Text] [PDF]
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B. W. Blaser, N. R. Schwind, S. Karol, D. Chang, S. Shin, S. Roychowdhury, B. Becknell, A. K. Ferketich, D. F. Kusewitt, B. R. Blazar, et al. Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft-versus-host disease but not for graft-versus-tumor activity Blood, October 1, 2006; 108(7): 2463 - 2469. [Abstract] [Full Text] [PDF]
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S. Wei, I. Kryczek, and W. Zou Regulatory T-cell compartmentalization and trafficking Blood, July 15, 2006; 108(2): 426 - 431. [Abstract] [Full Text] [PDF]
|
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M. Pelletier and D. Girard Differential Effects of IL-15 and IL-21 in Myeloid (CD11b+) and Lymphoid (CD11b-) Bone Marrow Cells J. Immunol., July 1, 2006; 177(1): 100 - 108. [Abstract] [Full Text] [PDF]
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M. P. Rubinstein, M. Kovar, J. F. Purton, J.-H. Cho, O. Boyman, C. D. Surh, and J. Sprent Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha} PNAS, June 13, 2006; 103(24): 9166 - 9171. [Abstract] [Full Text] [PDF]
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A. Jabbari and J. T. Harty Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype J. Exp. Med., April 17, 2006; 203(4): 919 - 932. [Abstract] [Full Text] [PDF]
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A. Le Bon, V. Durand, E. Kamphuis, C. Thompson, S. Bulfone-Paus, C. Rossmann, U. Kalinke, and D. F. Tough Direct Stimulation of T Cells by Type I IFN Enhances the CD8+ T Cell Response during Cross-Priming. J. Immunol., April 15, 2006; 176(8): 4682 - 4689. [Abstract] [Full Text] [PDF]
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G. Pulle, M. Vidric, and T. H. Watts IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival. J. Immunol., March 1, 2006; 176(5): 2739 - 2748. [Abstract] [Full Text] [PDF]
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E. Mortier, A. Quemener, P. Vusio, I. Lorenzen, Y. Boublik, J. Grotzinger, A. Plet, and Y. Jacques Soluble Interleukin-15 Receptor {alpha} (IL-15R{alpha})-sushi as a Selective and Potent Agonist of IL-15 Action through IL-15Rbeta/{gamma}: HYPERAGONIST IL-15{middle dot}IL-15R{alpha} FUSION PROTEINS J. Biol. Chem., January 20, 2006; 281(3): 1612 - 1619. [Abstract] [Full Text] [PDF]
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