IL-15 Receptor Maintains Lymphoid Homeostasis by Supporting Lymphocyte Homing and Proliferation

Lodolce, James P.; Boone, David L.; Chai, Sophia; Swain, Rachel E; Dassopoulos, Themistocles; Trettin, Shanthi; Ma, Averil

doi:10.1016/s1074-7613(00)80664-0

Cited by 1,170 publications

(1,121 citation statements)

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“…Although the importance of IL-15 in this process is undisputed [19,20,[22][23][24], it is unclear whether IL-15 1) acts on early NK cell precursors, 2) is only needed at the terminal steps of NK cell development or 3) is important role in maintaining lymphocyte proliferation and homeostasis. To investigate this process, we cultured human umbilical cord blood (UCB) CD34 + Lin − CD38 − primitive progenitors on AFT024.…”

Section: Resultsmentioning

confidence: 99%

“…IRF-1 knockout mice exhibit a severe NK deficiency, which is mediated by failure of transcriptional regulation of IL-15. In addition, knockout mice deficient in IL-15 itself or IL-15Rα have very few NK cells while IL-2 and IL-2Rα knockouts are unaffected [19,20]. In human studies, IL-15 is made by stroma and macrophages [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…In human studies, IL-15 is made by stroma and macrophages [21,22]. The importance of IL-15 in the homeostasis of NK [23,24] and T-cells provides further evidence of the physiologic role for this cytokine in the immune system [20]. These studies do not distinguish between the role of IL-15 in homeostatic expansion and survival versus differentiation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Indeed, mice deficient for signalling components of IL-7 and IL-15 (IL-7Ra À/À IL-2Rb À/À display a thymopoiesis block more closely resembling that of g c À/À mice than mice deficient for signalling components of IL-7 and IL-2 (IL-7Ra À/À IL-2Ra À/À ) or IL-7 and IL-4 (IL-7Ra À/À IL-4Ra À/À ) [39]. That fact that mice deficient for IL-15 or IL-15Ra display no obvious abnormalities in thymopoiesis [20,21] suggests a minor role for IL-15 in this species that is only evident when thymopoiesis is already impaired (such as in the absence of IL-7). The bioactive form of IL-15 is complexed with the IL-15Ra chain.…”

Section: Discussionmentioning

confidence: 99%

“…While IL-15 does not appear essential for thymopoiesis in mice [20,21], previous studies have shown that TEC subsets express IL-15 [22] and could ''trans-present'' IL-15/IL-15Ra complexes to developing thymocytes [23,24]. Since the bioavailability of human IL-15 in HIS mice appears limited [3], we next investigated the effect of exogenous IL-15 on human thymopoiesis in vivo.…”

Section: Effects Of Exogenous Human Il-15 Administration On Human Thymentioning

confidence: 99%

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

et al. 2011

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PortugalHuman Immune System (HIS) mice represent a novel biotechnology platform to dissect human haematopoiesis and immune responses. However, the limited human T-cell development that is observed in HIS mice restricts its utility for these applications. Here, we address whether reduced thymopoiesis in HIS mice reflects an autonomous defect in T-cell precursors and/or a defect in the murine thymic niche. Human thymocyte precursors seed the mouse thymus and their reciprocal interactions with murine thymic epithelial cells (TECs) led to both T-cell and TEC maturation. The human thymocyte subsets observed in HIS mice demonstrated survival, proliferative and phenotypic characteristics of their normal human counterparts, suggesting that the intrinsic developmental program of human thymocytes unfolds normally in this xenograft setting. We observed that exogenous administration of human IL-15/IL-15Ra agonistic complexes induced the survival, proliferation and absolute numbers of immature human thymocyte subsets, without any obvious effect on cell-surface phenotype or TCR Vb usage amongst the newly selected mature singlepositive (SP) thymocytes. Finally, when IL-15 was administered early after stem cell transplantation, we noted accelerated thymopoiesis resulting in the more rapid appearance of peripheral naïve T cells. Our results highlight the functional capacity of murine thymic stroma cells in promoting human thymopoiesis in HIS mice but suggest that the ''cross-talk'' between murine thymic stroma and human haematopoietic precursors may be suboptimal. As IL-15 immunotherapy promotes early thymopoiesis, this novel approach could be used to reduce the period of T-cell immunodeficiency in the post-transplant clinical setting. IntroductionSixty million years of evolution has generated important differences between the murine and human immune systems (HISs). As such, our knowledge of lymphocyte development, homeostasis and immune responses that is largely derived from mouse studies may not be directly applicable to man. The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection. TECs are classically divided into two specialized functional subsets, cortical (cTECs) and medullary (mTECs). While cTECs are important at early stages of T-cell development and mediate positive selection, mTECs are critical at later stages governing negative selection and providing survival signals to mature single-positive (SP) thymocytes [6,8,9]. The generation of these two functionally competent TEC compartments is a prerequisite ...

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Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells

2000

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NK T cells produce cytokines when their semi‐invariant TCR engages glycolipids associated with CD1d. The physiological consequences of NKT cell activation remain controversial, although they have been implicated in control of autoimmunity, parasites and tumors. We show here that specific activation of NKT cells in liver and spleen leads to a rapid induction of extensive NK cell proliferation and cytotoxicity. This NK cell activation is dependent, at least in part, on IFN‐γ production by NKT cells and IL‐12 production by antigen‐presenting cells. Remarkably, activation of NK cells by NKT cells is highly selective, since bystander T and B lymphocytes show transient expression of activation markers but almost no proliferation. Collectively our data suggest that CD1d‐dependent NKT cells regulate innate immunity by sampling blood‐borne glycolipid antigens and rapidly activating NK cells.

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IL-15 Receptor Maintains Lymphoid Homeostasis by Supporting Lymphocyte Homing and Proliferation

Cited by 1,170 publications

References 31 publications

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

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

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells

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