Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells.

Leclercq, Georges; Debacker, Veronique; Smedt, Magda De; Plum, Jean

doi:10.1084/jem.184.2.325

Cited by 140 publications

(97 citation statements)

References 58 publications

(78 reference statements)

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“…Molecular requirements for NK cell development were found only in growth factor-signaling pathways, whereas T cell maturation requires not only intact cytokine signaling, but also pre-TCR-and TCR-mediated signal transductions. Activation through IL-2R-␥ by IL-15 plays a critical step in early NK cell development (49). Targeted gene disruption of IL-15 or its transcription factor, IFN regulatory factor-1 resulted in the severe reduction in NK cell population (50).…”

Section: Discussionmentioning

confidence: 99%

Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation

Malarkannan

Regunathan

Chu

et al. 2007

The Journal of Immunology

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Activating receptors such as NKG2D and Ly49D mediate a multitude of effector functions including cytotoxicity and cytokine generation in NK cells. However, specific signaling events that are responsible for the divergence of distinct effector functions have yet to be determined. In this study, we show that lack of caspase recruitment domain-containing protein Bcl10 significantly affected receptor-mediated cytokine and chemokine generation, but not cytotoxicity against tumor cells representing “missing-self” or “induced-self.” Lack of Bcl10 completely abrogated the generation of GM-CSF and chemokines and it significantly reduced the generation of IFN-γ (>75%) in NK cells. Commitment, development, and terminal maturation of NK cells were largely unaffected in the absence of Bcl10. Although IL-2-activated NK cells could mediate cytotoxicity to the full extent, the ability of the freshly isolated NK cells to mediate cytotoxicity was somewhat reduced. Therefore, we conclude that the Carma1-Bcl10-Malt1 signaling axis is critical for cytokine and chemokine generation, although it is dispensable for cytotoxic granule release depending on the activation state of NK cells. These results indicate that Bcl10 represents an exclusive “molecular switch” that links the upstream receptor-mediated signaling to cytokine and chemokine generations.

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Section: Discussionmentioning

confidence: 99%

Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation

Malarkannan

Regunathan

Chu

et al. 2007

The Journal of Immunology

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“…In the absence of IL-7R function, high concentrations of IL-15 might be capable of expanding a few residual cells in the thymus that had rearranged the V γ 5 gene segment. However, in FTOC and suspension cultures of total iIELs, IL-15 expanded all γδTCR + cells, irrespective of TCR V gene usage (data not shown), ruling out the selective expansion of V γ 5 + cells by IL-15 as a likely explanation 26,27 . Alternatively, it was possible that IL-15, like IL-7, can regulate Tcrg locus chromatin accessibility, but that IL-15 specifically targets V γ 5 gene rearrangement.…”

Section: Il-15 Modulates Chromatin Accessibility Of V γ 5 Genementioning

confidence: 99%

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

2005

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AbstractγδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segmentspecific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.Intestinal intraepithelial lymphocytes (i-IELs) found within the intestinal epithelial layer are an essential component of mucosal immunity. Similar to T cell subsets in other lymphoid tissues, i-IELs are composed of two T cell types, αβ and γδT cells. In contrast to other tissues, however, γδT cells are prevalent in the mucosal epithelia of most vertebrates and are thought to be a major source of secreted factors necessary for the maintenance of tissue integrity subsequent to infection, transformation, or cell injury 1-3 .Despite the long history of i-IELs, their origin and ligand specificity remain uncertain. Earlier work has indicated that αβ i-IELs originate exclusively from the thymus in normal mice 4 , but whether γδ i-IELs are subject to similar developmental constraints is unclear. The majority of human and mouse γδ i-IELs express the homodimeric αα form of the CD8 coreceptor and exhibit restricted Variable (V) γ and V δ gene usage. In C57BL/6 (B6) mice, for example, V γ 5 expressing cells constitute the predominant i-IEL population in the small intestine [5][6][7] . Mouse strain-specific preferential usage of Tcrg and Tcrd genes among i-IELs arises from complex molecular and cellular controls with evidence for genetic linkage to the Tcrg, Tcrd and H2 loci 6,8,9 , but the exact mechanism is unknown. Two non-mutually exclusive mechanistic processes can be considered to account for the restricted TCR gene usage: cellular selection and programmed TCR gene rearrangement. A hallmark of adaptive immunity is the cellular selection process geared toward forming a population of cells with antigen receptor repertoires that can recognize the entire external universe of antigens. This selection pressure acts on immature cell subsets expressing randomly generated clonal antigen receptors. Although the TCR-driven selection shaping the αβTCR repertoire of conventional αβT cells constitutes a fundamental theme in immunology, whether a similar process is needed for γδT cell development, and specifically for γδ i-IELs, remains a matter of debate [10][11][12] .

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“…In the event that the NK T cells in the thymus may not be prevalent enough or are present in an immature stage as recently described for murine NK T cells (53,54), we sought to enrich for them by culturing thymocytes with the NK-stimulating cytokines IL-2 and IL-15 (55,56). After 7 days of culture of normal human postnatal thymocytes with IL-2 and IL-15 (20 ng/ml), both CD161 and CD56 expression on CD3 ϩ thymocytes and CD56 ϩ /CD161 ϩ conventional NK cells (CD3 Ϫ ) were increased (Fig.…”

Section: Canonical Nk T Cells Are Undetectable In the Human Thymusmentioning

confidence: 99%

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Gurney

Yang

Wilson

et al. 2002

The Journal of Immunology

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The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRγδ cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3+ cells but not the CD1d-restricted invariant Vα24/Vβ11/CD161+ NK T cells in the thymus. A subset of TCRγδ cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRγδ thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4+ TCRγδ cells. Similarly, CD4+CD161+ thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4−CD161+ thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4−CD161+ NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.

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Differential effects of interleukin-15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells.

Cited by 140 publications

References 58 publications

Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation

Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

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