TCR Signal Strength Influences αβ/γδ Lineage Fate

Hayes, Sandra M.; Li, LiQi; Love, Paul E.

doi:10.1016/j.immuni.2005.03.014

Cited by 243 publications

(289 citation statements)

References 46 publications

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“…Thus, signal strength does not only determine the outcome of positive and negative selection of DP cells; it appears also to be an important feature of b-selection. It has been suggested that strong and weak signals at the b-selection checkpoint favor development towards the cd and ab T cell lineages, respectively [25,26]. Our data is in agreement with this conclusion in that a certain minimal signal strength is required for facilitating b-selection through the ab (HY-) TCR.…”

Section: Discussionsupporting

confidence: 91%

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

et al. 2008

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A developmental block is imposed on CD25 + CD44 -thymocytes at the b-selection checkpoint in the absence of the pre T cell receptor (preTCR) a-chain, pTa. Early surface expression of a transgenic ab TCR has been shown to partially circumvent this block, such that thymocytes progress to the CD4 + CD8 + double-positive stage. We wanted to analyze whether a restricting MHC element is required for ab TCR-expressing doublenegative (DN) thymocytes to overcome the developmental block in pTa-deficient animals. We used the HY-I knock-in model that endows thymocytes with ab TCR expression in the DN compartment but has the advantage of physiological expression levels, in contrast to conventional TCR transgenes. On a pTa-deficient background, this HY-I TCR transgene 'rescued' CD25 + CD44 -thymocytes from apoptosis and enabled progression to later differentiation stages. On a non-selecting MHC background, however, pTa-deficient HY-I mice presented a pronounced reduction in numbers of splenocytes and thymocytes when compared to animals of selecting MHC genotype, showing that MHC restriction is necessary to drive HY-TCR-mediated rescue of pTa-deficient thymocytes.

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Section: Discussionsupporting

confidence: 91%

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

et al. 2008

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“…It was also observed that IL-17-producing ␥/␦ T cells are hardly induced in immunized joints, their DLNs, non-DLNs, and spleens of SKG mice (data not shown) 10 days after immunization with CFA plus type II collagen. Given that TCR signals in SKG mice are attenuated because of a point mutation in ZAP-70 (21), and differentiation of ␥/␦ T cells needs a strong signal via the TCR (48,49), there may be some defects in ␥/␦ T cell differentiation in SKG mice. This speculation was supported by data showing impaired development of specific subsets of ␥/␦ T cells in ZAP-70-knockout mice (50).…”

Section: Discussionmentioning

confidence: 99%

Gamma/delta T cells are the predominant source of interleukin‐17 in affected joints in collagen‐induced arthritis, but not in rheumatoid arthritis

Ito

Usui

Kobayashi

et al. 2009

Arthritis & Rheumatism

147

125

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Objective. Although interleukin-17 (IL-17Methods. IL-17-producing cells in the affected joints of mice with CIA were counted by intracellular cytokine staining during 6 distinct disease phases, and these cells were stimulated with various combinations of cytokines or specific antigens to determine the signaling requirements. Similar studies were performed using SKG mice with arthritis and patients with RA.Results. Gamma/delta T cells were the predomi-

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“…The thymus produces functional ab nTreg and gd T cells from common early precursors that follow distinct developmental pathways [7,26] but that end up sharing the unconventional property of being positively selected on high avidity signals [35][36][37][38], which presumably reflects their self-reactivity [21,39,40]. While the different homing properties of the two T-cell subsets may prevent their interaction in various tissues, gd cells may often come into contact with Treg in peripheral lymphoid organs, namely the spleen and lymph nodes (Supporting Information Fig.…”

Section: Discussionmentioning

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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TCR Signal Strength Influences αβ/γδ Lineage Fate

Cited by 243 publications

References 46 publications

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

Gamma/delta T cells are the predominant source of interleukin‐17 in affected joints in collagen‐induced arthritis, but not in rheumatoid arthritis

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

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