Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes

Narayan, Kavitha; Sylvia, Katelyn; Malhotra, Deepali; Yin, Catherine C.; Martens, Gregory W.; Vallerskog, Therese; Kornfeld, Hardy; Xiong, Na; Cohen, Nadia; Brenner, Michael B.; Berg, Leslie J.; Kang, Joonsoo

doi:10.1038/ni.2247

Cited by 187 publications

(275 citation statements)

References 51 publications

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“…The identification of γδ T cells producing IL-17 and details pertaining to their development have emerged only recently (14,18,25). Indeed, others have described unique developmental differences between the Vγ2 + and Vγ4 + γδ T-cell subsets in the dermis, despite their similar transcriptional profiles and common ability to produce IL-17 (16) and have shown that Vγ2 + , but not Vγ4 + , γδ T cells can be derived from adult bone marrow (39)(40)(41). Here we describe, to our knowledge, the first instance of a cytokine system whose absence enhances γδ-17-cell development.…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned above, γδ-17 cells exhibit limited TCR use, restricted to Vγ2 and Vγ4 expression (16). Thus, to gain further insight into the dysregulation of γδ-17 development in the absence of IL-15 vs. the absence of IL-15Rα, we examined the CD44 lo/int IL-17 + γδ-17 precursor population for Vγ expression.…”

Section: Resultsmentioning

confidence: 99%

“…15). The γδ-17 subset of γδ T cells has a restricted TCR use that is largely limited to Vγ2 and Vγ4 expression (Garmin nomenclature; Vγ4 and Vγ6 in Tonegawa nomenclature) and a molecularly distinct gene expression profile (16). Considering the strictly regulated developmental progression of γδ T-cell subsets (17), the vast majority of γδ-17 cells are known to emerge during a limited window early in ontogeny, ∼E16.5 up to shortly after birth (18).…”

Section: Il-15rα | γδ T Cells | Il-17mentioning

confidence: 99%

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IL-15 receptor α signaling constrains the development of IL-17–producing γδ T cells

Colpitts

Puddington

Lefrançois

2015

Proc. Natl. Acad. Sci. U.S.A.

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The development and homeostasis of γδ T cells is highly dependent on distinct cytokine networks. Here we examine the role of IL-15 and its unique receptor, IL-15Rα, in the development of IL-17-producing γδ (γδ-17) T cells. Phenotypic analysis has shown that CD44 high γδ-17 cells express IL-15Rα and the common gamma chain (CD132), yet lack the IL-2/15Rβ chain (CD122). Surprisingly, we found an enlarged population of γδ-17 cells in the peripheral and mesenteric lymph nodes of adult IL-15Rα KO mice, but not of IL-15 KO mice. The generation of mixed chimeras from neonatal thymocytes indicated that cell-intrinsic IL-15Rα expression was required to limit IL-17 production by γδ T cells. γδ-17 cells also were increased in the peripheral lymph nodes of transgenic knock-in mice, where the IL-15Rα intracellular signaling domain was replaced with the intracellular portion of the IL-2Rα chain (that lacks signaling capacity). Finally, an analysis of neonatal thymi revealed that the CD44 lo/int precursors of γδ-17 cells, which also expressed IL-15Rα, were increased in newborn mice deficient in IL-15Rα signaling, but not in IL-15 itself. Thus, these findings demonstrate that signaling through IL-15Rα regulates the development of γδ-17 cells early in ontogeny, with long-term effects on their peripheral homeostasis in the adult.B oth αβ and γδ T cells rely heavily on cytokine signaling for their development and survival. Many of these cytokines belong to the IL-2 cytokine family, whose receptors all share a common γ receptor chain (γ c ; CD132). Among these, IL-15 has a unique, nonredundant role in both T-cell and natural killer (NK)-cell biology, such that CD8 + memory T cells and NK cells are absent in IL-15-deficient environments (1, 2). The predominant mechanism through which IL-15 functions is termed transpresentation, whereby IL-15 is preassociated with its specific α-chain (IL-15Rα) inside the cell and presented at the cell surface in trans to a responding cell expressing γ c and IL-2/15Rβ (CD122) (3-6). IL-15 is unique among its family members owing to its ability to act either in cis or in trans. Whether or not direct signaling (in cis) via IL-15Rα plays a significant biological role in immunobiology has not been resolved (7-11).Certain populations of γδ T cells are known to be sensitive to the availability of IL-15 for their development and/or survival. A population of specialized γδ T cells called dendritic epidermal T cells are absent from the skin of IL-15 knockout (KO) and IL-15Rα KO mice (12, 13). The CD8αα + γδ T-cell receptor (TCR) intraepithelial lymphocytes are also decreased in these two KO mouse strains (1, 2). In addition, IL-15 KO mice have a reduced population of IFN-γ + γδ T cells in the peritoneum (14). All of these populations express CD122, suggesting they can receive IL-15-dependent signals via transpresentation.Recently, γδ T cells have emerged as important contributors to the generation of immune responses. The innate-like γδ T cells that produce IL-17 (γδ-17 cells) have been implicated in immune re...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Il-15rα | γδ T Cells | Il-17mentioning

confidence: 99%

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IL-15 receptor α signaling constrains the development of IL-17–producing γδ T cells

Colpitts

Puddington

Lefrançois

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…On the other hand, interferon‐ γ (IFN‐ γ ) production is associated with V γ 1 + , V γ 5 + and V γ 7 + γδ T cells. Although overall gene expression patterns are similar between V γ 4 + and V γ 6 + subsets,34 each subset has distinct features (Fig. 1).…”

Section: γδ T‐cell Subsets and Their Developmentmentioning

confidence: 94%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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“…2 cd T cells expressing different Vcs have different effects on the immune responses. 8 Recent studies revealed a correlation between TCR-Vc expression and functional differentiation, 9,10 thus emphasizing the biological significance of the cd TCR segregation in the mouse. Nevertheless, specific evidence concerned with IL-17 producing cd T cells suggests that, at least in this case, the correlation between cd TCR expression and function is merely coincidental-waves of cd T cells expressing certain TCRs coincide with a thymic environment that temporarily favors TH17 differentiation.…”

Section: The CD T-cell Receptorsmentioning

confidence: 99%

Diversity of γδ T-cell antigens

2012

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In the last two decades, it has become clear that cd T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, cd antigens as a whole resemble more the antigens recognized by antibodies than those recognized by ab T cells. Because of this antigenic diversity, no single mechanism-such as the major histocompatibility complex (MHC) restriction of ab T cells-is likely to provide a basis for all observed T-cell antigen receptor (TCR)-dependent cd T-cell responses. Furthermore, available evidence suggests that many individual cd T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of cd T-cell populations, and thus generate a more efficient immune response.

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Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes

Cited by 187 publications

References 51 publications

IL-15 receptor α signaling constrains the development of IL-17–producing γδ T cells

IL-15 receptor α signaling constrains the development of IL-17–producing γδ T cells

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Diversity of γδ T-cell antigens

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