T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse

Moran, Amy E.; Holzapfel, Keli L.; Xing, Yan; Cunningham, Nicole; Maltzman, Jonathan S.; Punt, Jennifer A.; Hogquist, Kristin A.

doi:10.1084/jem.20110308

Cited by 916 publications

(1,218 citation statements)

References 56 publications

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“…We also noted a difference of CD5 expression between the subsets (Supplemental Fig. 2), in agreement with previous work on higher tonic TCR signaling (47) and ensuing CD5 expression by CD4 + T cells (48,49). Following incubation, the cells had become blasts and had initiated proliferation because they had divided once on average (Fig.…”

Section: Comparable Activation Of and And Ot1 T Cell Activation In Vitrosupporting

confidence: 91%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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Section: Comparable Activation Of and And Ot1 T Cell Activation In Vitrosupporting

confidence: 91%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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“…Although dispensable for the persistence of memory T helper cells, T Reg cells (perhaps as a consequence of self-antigen recognition) seem to be constitutively activated and require interactions through their TCR and CD28 to maintain effector populations [66][67][68][69][70] . However, strong TCR stimulation of T Reg cells by an autoantigen that instigates autoimmune disease can transiently destabilize their FOXP3 expression 71 , whereas the chronic stimulation of autoreactive effector T cells may induce FOXP3 expression in these cells and promote immune tolerance 72 .…”

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confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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“…5B). As altered TCR signals [31,[70][71][72]] might contribute to this phenotype, we explored the regulation of the TCR-specific immediate early gene Nr4a1/Nur77 [31,73], which has been used as readout for TCR signaling strength [74]. To this end, we crossed slp-76 ace/ace with Nur77 GFP mice, in which GFP is expressed in T cells after TCR-specific engagement [74].…”

Section: The Reduced Tcr Signal Strength Is Associated With An Enhancmentioning

confidence: 99%

“…5G). Furthermore, the expression of PD-1 that transduces inhibitory signals [75] and correlates with the strength of TCR signaling [74], was significantly reduced on iNKT cells within all tissue sites of slp-76 ace/ace mice (Supporting Information Fig. 3B).…”

mentioning

confidence: 99%

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

et al. 2016

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TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76 ace/ace mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP −/− iNKT cells, slp-76 ace/ace iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP −/− mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76 ace/ace mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.Keywords: ADAP r Cytokine r iNKT cell r Integrin r slp-76Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2016Immunol. . 46: 2121Immunol. -2136 Introduction iNKT cells express a panoply of NK-cell receptors [1] and a canonical TCR through which they recognize (glyco-)lipid antigens [2]. iNKT cells activate similar signaling cascades after TCR ligation like other T lymphocytes [3], but utilize unique transcription factors for their development such as the promyelocytic leukemia zinc finger (PLZF) [4][5][6]. According to two different developmental models PLZF characterizes distinct maturation stages and polarized subsets. The sequential lineage model suggests a gradual decrease of PLZFexpression following selection of iNKT cells which show a Th2-dominated cytokine profile during earlier and a Th1-dominated cytokine profile during later stages of intrathymic maturation [1,7]. The second model describes lineage diversification and simultaneous differentiation into Th1-, Th2-, or Th17-polarized subsets that are defined by the level of PLZF-expression [8]. Although many iNKT cells release both Th1 and Th2 cytokines on a single cell level [9], the production of IL-17 and IFN-γ is mutually exclusive within NK1.1 − cells [10][11][12]. Several transcription factors, such as Egr2, T-bet, ThPOK, Id2, Id3, and the Tec kinases Itk and Rlk have been implicated in the differentiation of iNKT cell subsets [6,8,[13][14][15][16][17] which home to distinct tissues. Specifically, liver and spleen constitute the main source for the Th1-polarized sublineage which is PLZF low . Th2-or ...

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T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse

Abstract: Generation of a Nur77 reporter mouse is used to demonstrate TCR signal strength during thymic selection and peripheral maintenance of conventional and nonconventional T cell subsets and presents a novel tool for studying antigen receptor activation in vivo.

Cited by 916 publications

References 56 publications

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

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