Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis

Burkett, Patrick R.; Koka, Rima; Chien, Marcia; Chai, Sophia; Boone, David L.; Ma, Averil

doi:10.1084/jem.20041389

Cited by 341 publications

(348 citation statements)

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“…During the first month after transplantation, T cells are generated by peripheral expansion rather than through the hematopoiesis-dependent thymic pathway [44][45][46]. This expansion is driven by IL-7 and IL-15 of which the latter also regulates the homeostasis of NK cells [47,48]. CD8 1 memory effector T cells are known to restrict IL-15-dependent homeostasis of gd-T cells [49,50].…”

Section: Discussionmentioning

confidence: 99%

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

et al. 2010

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We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56 dim CD16 bright NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56 bright NK cells (ptCD56 bright ) differed from CD56 bright NK cells in normal controls (CD56 bright ) in being HLA-DR-and perforin-positive, CCR7 À , CD27 À , CD127 À and mostly c-kit À . CD56 bright from normal controls stimulated by IL-15 in vitro (NK ) acquired all the characteristics distinguishing CD56 bright from ptCD56 bright . IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56 bright , CD56 bright and NK responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-c production in ptCD56 bright , whereas CD56 bright responded only to IL-12 plus IL-15. Hence, ptCD56 bright have all the features of cytokine-stimulated CD56 bright . Because only patients with low numbers of T cells had high numbers of ptCD56 bright , we conclude that ptCD56 bright are activated CD56 bright that expand while competing with T cells for the elevated post-transplant level of IL-15.Key words: HSC transplantation . Human . Natural killer cells IntroductionIn humans, most lymphocytes without rearranged antigenreceptors express CD56 and are referred to as NK cells. Accordingly, they can be identified on the basis of a CD3 À CD56 1 phenotype [1][2][3], which excludes the subpopulation of T cells that coexpress CD56. However, this long-established definition of NK cells may be inadequate because CD3 À CD56 1 lymphocytes are heterogeneous and capable of exerting various effector functions other than killing cells with altered expression of self-MHC. Furthermore, many CD3 À CD56 1 lymphocytes do not lyse NK-cell targets when tested ex vivo and only acquire lytic activity after in vitro stimulation with cytokines. In fact, the large granular CD3 À CD56 1 lymphocytes with ''natural'' cytotoxicity that express low levels of CD56 (CD56 dim ) and high levels of the Fcg-receptor type III (CD16) [1][2][3][4] represent only a minority of all of the CD3 À CD56 1 lymphocytes in the body [5,6]. CD56 dim that provide first-line defense against viruses [7,8] 3246less abundant population of NK cells in peripheral blood expresses much higher levels of CD56 (CD56 bright ), the receptor for IL-7 (CD127), the receptor for SCF c-kit, the lymph nodehoming receptor CCR7, and displays only little cytolytic activity [3][4][5][9][10][11][12]. Approximately, half of the CD56 bright in peripheral blood express CD27, a marker virtually absent from CD56 dim [13][14][15]. Hence, CD56 bright in peripheral blood are identical or closely related to the NK cells residing in secondary lymphoid organs (SLO) that produce cytokines to guide the adaptive immune response [4-6,...

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Section: Discussionmentioning

confidence: 99%

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

et al. 2010

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“…IL-2 is a soluble factor produced by activated T cells [21] whereas IL-15 is complexed with the IL-15 receptor a chain (IL-15Ra) and presented on the cell surface [22][23][24]. IL-15/IL-15Ra complexes undergo recycling without lysosomal degradation and therefore, membrane-bound IL-15 is well suited to provide continuous survival signals for receptive T cells [25][26][27]. Moreover, signaling by IL-15 but not IL-2 has been shown to upregulate the antiapoptotic protein Bcl-x L in anti-CD3-stimulated human T cells [18].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

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“…The IL-15 independent effects need to be interpreted carefully. It is now well established that IL-15 signaling may be amplified by interaction with membrane bound or soluble IL-15Rα resulting in a "hyper IL-15" signal [41][42][43][44][45]. We questioned whether murine IL-15 was produced by the stroma itself, which could interact with IL-15Rα to account for our findings.…”

Section: Discussionmentioning

confidence: 85%

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

McCullar

Oostendorp

Panoskaltsis‐Mortari

et al. 2008

Experimental Hematology

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Objective-Human NK cell maturation involves the orderly acquisition of NK cell receptors. Our aim was to understand how stromal interactions and cytokines are important in this developmental process.Methods-Human UCB CD34 + /Lin − /CD38 − cells were cultured on two murine stromal cell lines (AFT024 and EL08-1D2) in a switch culture to study NK cell development.Results-When human progenitors were cultured on AFT024 with IL-3 and Flt3-L in the absence of IL-15, NK cell differentiation occurred, albeit at low frequency. These conditions favored the accumulation of CD56 − NK cell precursors (CD34 + CD7 − , CD34 + CD7 + and CD34 − CD7 + cells), which are populations rare in adult blood but abundant in fresh UCB. In secondary culture, addition of IL-3 or IL-3+Flt3L to IL-15 increased the absolute number of CD56 + NK cells from precursors and the acquisition of CD94 and KIR. To further explore the microenvironment in early NK cell maturation, a cell line derived from murine embryonic liver (EL08-1D2) was studied. NK cell development and KIR acquisition was superior with EL08-1D2 which supported the differentiation of NK cell precursors, NK cell commitment, and proliferation.Conclusion-Although the earliest events in NK cell maturation do not require exogenous human IL-15, it is required at a later stage of NK cell commitment. At a minimum, murine stroma, IL-3, and Flt3-L are required to recapitulate early NK cell development and differentiation into distinct NK cell precursors. EL08-1D2 induces KIR acquisition suggesting that extrinsic signals in NK cell development are conserved between mouse and man.

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Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis

Cited by 341 publications

References 34 publications

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

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Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis

Cited by 341 publications

References 34 publications

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

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CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells