Essential function for the GTPase TC21 in homeostatic antigen receptor signaling

Delgado, Pilar; Cubelos, Beatriz; Calleja, E.; Martínez, Núria; Ciprés, Angel; Mérida, Isabel; Bellas, Carmen; Bustelo, Xosé R.; Alarcón, Balbino

doi:10.1038/ni.1749

Cited by 108 publications

(141 citation statements)

References 51 publications

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“…This compromised pathway may also contribute to the slow cell death we observed, because homeostatic survival signals are not properly transduced. In support of this, a recently identified molecule required for homeostatic signaling in T and B cells is a member of the ras family (53).…”

Section: Discussionmentioning

confidence: 99%

Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

Han

Asoyan

Rabenstein

et al. 2010

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

123

127

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It is currently not understood how some chronic infections exhaust antigen-specific T cells over time and which pathogen components contribute to exhaustion. Here, we dissected the behavior of primed CD4 + T cells exposed to persistent antigen using an inducible transgenic mouse system that allowed us to control antigen presentation as the only experimental variable, independent of the persistent inflammation and disease progression that complicate infectious models. Moreover, this system restricted antigen presentation to dendritic cells (DCs) and avoided confounding B, CD8 + T, or innate cell responses. When antigen presentation was extended beyond the expansion phase, primed CD4 + T cells survived, but exhibited reduced memory functionality in terms of their proliferative capacity and cytokine expression potential. The effect was antigen dose and time dependent, not associated with increased PD-1 expression or reduced calcium influx, but impaired Jun phosphorylation in response to TCR engagement. Upon antigen removal, the cells regained the ability to proliferate, but remained unable to produce high levels of IL-2 and TNF-α. These data show that persistent antigen by itself rapidly induces a dysfunctional state in CD4 + T cells that is only partially reversible upon antigen removal. These findings have implications for vaccine optimization and for the possible reinvigoration of CD4 + T cells during chronic infection.anergy | immunological memory | immunological tolerance | T helper cells

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Section: Discussionmentioning

confidence: 99%

Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

Han

Asoyan

Rabenstein

et al. 2010

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

123

127

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“…By targeting Syk, FcRL4 may leave intact tonic BCR signaling necessary for B-cell survival while blocking antigen-driven BCR activation. Recent results from Rajewsky et al 26 and Alarcó n et al 27 provided evidence that tonic signaling is dependent on PI3K activation and that PI3K may be recruited to the ITAMS of the BCR through the GTPase TC21. These results suggest that tonic BCR survival signaling may be independent of antigen-induced BCR signaling and would be unaffected by FcRL4 attenuation of Syk phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling

Sohn

Krueger

Davis

et al. 2011

Blood

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Ehrhardt et al first described FcRL4 to mark a unique population of memory B cells (MBCs) in human lymphoid tissues near epithelial surfaces that had distinctive functional capabilities. 3 In humans, FcRL4 ϩ MBCs lack CD27, the classic marker for MBCs, and, compared with FcRL4 Ϫ MBCs, express more CD20 and less CD21 and have strongly up-regulated CCR1 and CCR5 that may play a role in their tissue localization. FcRL4 ϩ and FcRL4 Ϫ MBCs have undergone isotype switching and somatic hypermutation to similar levels, but neither expresses transcription factors associated with plasma-cell differentiation. FcRL4 ϩ MBCs do not proliferate in response to BCR cross-linking, but differentiate into plasma cells in response to IL-2, IL-10, and CD40 ligand. These results suggest that FcRL4 ϩ MBCs have dampened signaling through the BCR while maintaining their sensitivity to cytokines and T-cell help. Subsequent comparative transcriptome and proteome analyses revealed that FcRL4 ϩ and FcRL4 Ϫ MBCs had distinctive expression of a variety of genes providing a signature for FcRL4 ϩ MBCs, 4 including genes encoding: (1) cell-surface markers, including CD11c, CCR1, CCR5, RANKL, and DLL1; (2) regulators of the cell cycle; (3) signal-transduction molecules such as FgR and Hck; and (4) transcription factors, including RUNX2 and SOX5. The investigators of that study concluded that these distinctive MBCs residing in close proximity to epithelial tissues in mucosal lymphoid tissues may play an important role in healthy individuals in humoral immune responses at epithelial boundaries in the body in close proximity to the natural microflora and sites of invading pathogens.Moir et al described a similar population of FcRL4 ϩ MBCs in the peripheral blood of HIV-infected viremic individuals. 5 Compared with FcRL4 Ϫ MBCs, these FcRL4 ϩ MBCs expressed high levels of inhibitory receptors, including CD22 and CD85j. The profile of trafficking receptors was similar to that described for FcRL4 ϩ MBCs in tissues by Ehrhardt et al,3,4 suggesting that these FcRL4 ϩ MBCs in the blood of HIV-viremic individuals were migrating from lymphoid tissues to chronically inflamed tissues. Compared with FcRL4 Ϫ MBCs, FcRL4 ϩ MBCs from HIV-viremic individuals showed reduced proliferation and differentiation into plasma cells in response to the cytokines IL-2 and IL-10, T-cell help in the form of CD40L, and BCR cross-linking. 5 Because the pattern of expression of inhibitory and homing receptors by FcRL4 ϩ MBCs in HIV-viremic individuals was similar to that described for virus-specific CD8 ϩ T-cell exhaustion in chronic lymphocytic choriomeningitis virus infections in mice and in HIV-viremic individuals, [6][7][8] Moir et al called these FcRL4 ϩ MBCs "exhausted MBCs." 5,9 HIV-specific B cells were enriched in the FcRL4 ϩ MBC population, in contrast to influenza-specific B cells, which were concentrated in the FcRL4 Ϫ MBC population, 5 suggesting that exhaustion of MBCs was antigen driven and may The online version of this article contains a data supplement.The public...

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“…More recently, TC21, a closely related small GTPase of R-Ras, has been shown to bind both T-and B-cell antigen receptors and play a role in homeostatic proliferation and survival of these immune cell types. 18 In this study, we provide evidence of R-Ras expression in multiple murine immune cells that include DCs. Characterization of an Rras Ϫ/Ϫ mouse line revealed multiple defects in DCs, including impaired maturation and T-cell priming, attenuated activation of intracellular signaling pathways downstream of Toll-like Receptor 4 (TLR4), and reduced formation of stable immunologic synapses between DCs and T cells.…”

Section: Introductionmentioning

confidence: 93%

R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

Singh

Hashimoto

Yan

et al. 2012

Blood

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R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that RRas is expressed by lymphoid and nonlymphoid tissues and drastically upregulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Rasdeficient mouse strain. We found that tumors induced in Rras ؊/؊ mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras ؊/؊ mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras ؊/؊ DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras- IntroductionDendritic cells (DCs) are potent antigen-presenting cells with key roles in initiating antigen-specific immune responses. 1 Although numerous reports have implicated members of the RAS superfamily of GTP-binding proteins in DC biology, 2 a complete understanding of their individual roles is still lacking. Small GTPases traditionally operate as molecular switches, being inactive in the GDP-bound state and active in the GTP-bound state, therein conferring signaling function through interactions with their downstream effectors. 3 Indeed, several small GTPases have been shown to play critical roles in immune cell functions by regulating actin cytoskeleton-dependent processes. [4][5][6][7][8][9][10] Small GTPases Rap1, Rac1/2, and Cdc42, with the latter 2 being part of the RHO family of GTPases, have been demonstrated to be important in DC biology. Active Cdc42 can reactivate endocytosis in mature DCs, whereas microinjection of a dominant negative Cdc42N17 mutant abrogates the uptake of dextran. 9 Interestingly, it was demonstrated in DCs that levels of active Cdc42 and Rac were not increased in response to lipopolysaccharide (LPS). 11 However, using mature DCs from Rac1 and Rac2 double-knockout mice (Rac1/2 Ϫ/Ϫ ), Rac1 and Rac2 were shown to be critical for dendrite formation and T-cell activation. 12 In addition, RAPL, a downstream effector of Rap1, has been shown to be critical for both lymphocyte and DC migration and adhesion. 5,6 Although both Rap1 and Cdc42/Rac GTPases are clearly involved in DC biology, little is known concerning the role of other key members of the Ras subfamily.R-Ras is a small GTPase that belongs to the Ras subfamily and shares approximately 55% amino acid sequence similarity with the RAS proto-oncogenes, H-RAS, N-RAS, and K-RAS (collectively referred to as Ras herein). 13,14 Distinctively, R-Ras possesses a unique 26-amino acid sequence in the aminoterminus that is necessary for Rac activation and Rac-dependent cell spreading. 15 Furthermore, active R-Ras in macrophages has been shown to positively regulate phagocytosis of C3bi-opsonized particles via the in...

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Essential function for the GTPase TC21 in homeostatic antigen receptor signaling

Cited by 108 publications

References 51 publications

Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling

R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

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Essential function for the GTPase TC21 in homeostatic antigen receptor signaling

Cited by 108 publications

References 51 publications

Role of antigen persistence and dose for CD4+T-cell exhaustion and recovery

Role of antigen persistence and dose for CD4+T-cell exhaustion and recovery

FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling

R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

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Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery

Role of antigen persistence and dose for CD4⁺T-cell exhaustion and recovery