Loss of the LAT Adaptor Converts Antigen-Responsive T Cells into Pathogenic Effectors that Function Independently of the T Cell Receptor

Mingueneau, Michaël; Roncagalli, Romain; Grégoire, Claude; Kissenpfennig, Adrien; Miazek, Arkadiusz; Archambaud, Cristel; Wang, Ying; Perrin, Pierre; Bertosio, Elodie; Sansoni, Amandine; Richelme, Sylvie; Locksley, Richard M.; Aguado, Enrique; Malissen, Marie; Malissen, Bernard

doi:10.1016/j.immuni.2009.05.013

Cited by 103 publications

(141 citation statements)

References 42 publications

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“…Although Raf and MEK1 have been shown to mediate ERK activation by Cdc42 (43, 44), we did not find significant alterations in Raf and MEK1 activities in Cdc42 −/− T cells, suggesting that Cdc42 inhibition of ERK activation is independent of Raf and MEK1. In addition to the impact on JNK, Cdc42 also may suppress ERK activation through other mechanisms: (i) by upregulation of negative regulators of T-cell activation such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), IκB, and suppressor of cytokine signaling 1 (Socs1) (45) and/or (ii) by activating LAT adaptor, removal of which recently was shown to cause a lymphoproliferative phenotype (46).…”

Section: Discussionmentioning

confidence: 99%

Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

Guo¹,

Hildeman²,

Tripathi³

et al. 2010

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

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T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown. Here we demonstrate that T cell-specific deletion of cell-division cycle 42 ( Cdc42 ) GTPase causes a profound loss of mature T cells. Deletion of Cdc42 leads to a markedly increased expression of growth factor independence-1 (Gfi-1) and represses expression of IL-7Rα. In the absence of Cdc42 , aberrant ERK1/2 MAP kinase activity results in enhanced, TCR-mediated T-cell proliferation. In vivo reconstitution of effector-binding–defective Cdc42 mutants and the effector p21 protein-activated kinase 1 (PAK1) into Cdc42 -deficient T cells showed that PAK1 is both necessary and sufficient for Cdc42-regulated T-cell homeostasis. Thus, T-cell homeostasis is maintained through a concerted regulation of Gfi-1–IL-7R–controlled cytokine responsiveness and ERK-mediated TCR signaling strength by the Cdc42-PAK1 signaling axis.

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Section: Discussionmentioning

confidence: 99%

Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

Guo¹,

Hildeman²,

Tripathi³

et al. 2010

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

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“…In LAT-deficient Jurkat cells, c-Cbl is hyperphosphorylated upon TCR stimulation (Finco et al 1998;Mingueneau et al 2009) and phosphorylated c-Cbl has been implicated in negative regulation of TCR signal transduction (Boussiotis et al 1997;Murphy et al 1998). In addition, consistent with its role as an E3-ubiquitin ligase in several signaling systems, c-Cbl has been implicated in ubiquitylation of the TCRz and CD3d chains of the TCR as well as the signaling proteins ZAP-70, LAT, PLC-g1, PI3K, Vav, and PKC-u in T cells (Weissman 2001;Duan et al 2004;Balagopalan et al 2007).…”

Section: Plc-g1 Binds Y132 Of Lat and Mediates Transcriptional Activamentioning

confidence: 99%

“…Altered signaling in LAT Y136F T cells consists of decreased TCR-induced calcium flux and other events downstream of PLC-g1 (Sommers et al 2002). Reports of Erk1/2 activation in LAT Y136F T cells have been variable (Sommers et al 2002;Mingueneau et al 2009;Miyaji et al 2009), most likely because of different methods of in vitro activation and age of the animals from which the T cells were derived. However, a report by Miyaji et al showed that Erk activation played an important role in lymphoproliferative disease in LAT Y136F mice (Miyaji et al 2009).…”

Section: In Vivo Functions Of Lat Phosphotyrosines and Cysteinesmentioning

confidence: 99%

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The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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“…8B, are responsible for the induction of colitis when transferred in the absence of Treg cells. Antigenic peptides derived from the enteric bacteria and presented by MHCII molecules have been shown to be responsible for this TCR-driven fast proliferation whereas the slow proliferation is independent of MHCII molecules and IL-7-driven [26][27][28][29][30]. We took advantage of this model to determine whether upon transfer into Cd3e 5/ 5 x MHCII / mice, MLN-resident inflammatory M s isolated from MHCII-sufficient, colitic mice were capable of rescuing the fast proliferation of cotransferred CD4 + T cells and their differentiation into IFN-γ-producing effectors.…”

mentioning

confidence: 99%

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

et al. 2012

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Dendritic cells (DCs) and monocyte-derived macrophages (M s) are key components of intestinal immunity. However, the lack of surface markers differentiating M s from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, M s can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating M s and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C hi monocytes to intestinal M s. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory M s endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. Eur. J. Immunol. 2012. 42: 3150-3166 HIGHLIGHTS 3151 IntroductionThe intestinal lamina propria (LP) contains cells that express high levels of CX 3 CR1, the receptor for the fractalkine chemokine [1,2]. Based on their monocytic origin and on their inability to migrate to the mesenteric lymph nodes (MLNs) such CX 3 CR1 hi cells have been defined as macrophages (M s) [1][2][3]. CX 3 CR1 hi M s contribute to the intestinal LP homeostasis through the production of anti-inflammatory cytokines and the clearance of commensal bacteria that breach the epithelial barrier [4]. In contrast, during intestinal inflammation, microenvironmental signals promote the differentiation of extravasated monocytes into proinflammatory M s with the ability to produce interleukin (IL)-12, IL-23, tumor necrosis (TNF)-α and inducible nitric oxide synthase (iNOS) [5][6][7]. However, little is known about the developmental trajectories that lead extravasated monocytes to either antior proinflammatory intestinal M s. This is primarily due to the fact that a surface marker permitting unequivocal identification of M s within the intestine and their distinction from dendritic cells (DCs) is lacking. The interstitial DCs (Int-DCs) present throughout the LP derive from blood precursors known as pre-DCs [2]. Under steady-state conditions, the Int-DCs found in the intestinal LP induce oral tolerance by carrying antigens originating from food or from harmless bacteria to the MLNs [8,9]. The CD103 + Int-DCs found in the steady-state LP have the selective ability to express aldehyde dehydrogenase (ALDH) and thereby produce retinoic acid (RA). As a result, upon migration to MLNs they trigger the differentiation of naive CD4 + T cells specific for food and microbiota antigens into induced Foxp3 + regulatory T (iTreg) cells [10][11][12][13]. In contrast, the Int-DCs that develop in inflamed LP upon exposure to pathogens lose their capacity to generate iTreg cells and, upon migration to the MLNs, trigger the differentiation of naive, antigen-responsive CD4 + T cells into T helper type 1 (Th1) cells that are specific for the invading patho...

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Loss of the LAT Adaptor Converts Antigen-Responsive T Cells into Pathogenic Effectors that Function Independently of the T Cell Receptor

Cited by 103 publications

References 42 publications

Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

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