γδ T cell homeostasis is established in competition with αβ T cells and NK cells

French, Jena D.; Roark, Christina L.; Born, Willi K.; O’Brien, Rebecca L.

doi:10.1073/pnas.0507520102

Cited by 59 publications

(83 citation statements)

References 62 publications

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“…We adapted this system to test the effect of Treg on gd-cell expansion in Rag2-deficient animals; we added P. berghei ANKA infection as an extra stimulus (1 day after the injection of lymphocytes) due to the relatively poor homeostatic expansion of gd cells (data not shown) [32]. In this adapted model, Teff and Treg engrafted and expanded comparably after 4 days ( Fig.…”

Section: In Vivo Suppression Of Cd-t-cell Expansion By Tregmentioning

confidence: 99%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

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Section: In Vivo Suppression Of Cd-t-cell Expansion By Tregmentioning

confidence: 99%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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“…Since the lack of B cells influenced the number of splenic NK cells, which are dependent on IL-15 for their survival [21][22][23], we tested whether B cell deficiency had an impact on T cell populations, which similarly depend on IL-15 [5,24,26]. In addition to NK cells, the numbers of TCRcd were significantly decreased in lMT -/-as compared to B6 mice (Fig.…”

Section: Nk Cell Production and Turnovermentioning

confidence: 99%

“…Similar to NK cells, memory CD8 T cells [5,24], TCRab NKT cells [25] and TCRcd cells [26] depend on IL-15 for their peripheral maintenance. However, while TCRcd and NK cells were reduced, the proportion of CD8 + memory T cells (of naive CD8 + T cells) is normal in B cell-deficient mice.…”

Section: Nk Cells In B Cell-deficient Micementioning

confidence: 99%

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T and B lymphocytes exert distinct effects on the homeostasis of NK cells

2006

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There is growing evidence that lymphocytes impact the development and/or function of other lymphocyte populations. Based on such observations we have tested whether the NK cell compartment was phenotypically and functionally altered in the absence of B and/or T cells. Here we show that T cell deficiency significantly accelerates BM NK cell production and the subsequent seeding of splenic and liver NK cell compartments. In contrast, B cell deficiency reduces splenic NK cell survival. In the absence of T and B cells, the size of the NK cell compartments is determined by the combination of these positive and negative effects. Even though NK cell homeostasis is significantly altered, NK cells from T and/or B cell-deficient mice show a normal capacity to kill a susceptible target cell line and to produce IFN. Nevertheless, we noted that the usage of MHC class Ispecific Ly49 family receptors was significantly altered in the absence of T and/or B cells. In general, B cell deficiency expanded Ly49 receptor usage, while T cell deficiency exerted both positive and negative effects. These findings show that B and T cells significantly and differentially influence the homeostasis and the phenotype of NK cells.

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“…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]. Furthermore, NK cells and CD8 1 T cells compete for IL-15 in lymphopenic mice [51].…”

mentioning

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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γδ T cell homeostasis is established in competition with αβ T cells and NK cells

Cited by 59 publications

References 62 publications

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

T and B lymphocytes exert distinct effects on the homeostasis of NK 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

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γδ T cell homeostasis is established in competition with αβ T cells and NK cells

Cited by 59 publications

References 62 publications

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

T and B lymphocytes exert distinct effects on the homeostasis of NK cells

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

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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