Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Ishida, Daisuke; Yang, Hailin; Masuda, Kyoko; Uesugi, Kanami; Kawamoto, Hiroshi; Hattori, Masao; Minato, Nagahiro

doi:10.1073/pnas.1834525100

Cited by 41 publications

(53 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data show that the inhibition of Rap1 activation via Rap1GAP1 expression enhanced TCR-dependent ERK activation, IL-2 production, proliferation, and CD69 expression, consistent with a role of endogenous Rap1 to limit T-cell activation. These data complement nicely those results seen with peripheral T cells from Spa-1-null mice, which displayed decreased ERK activity and developed anergy associated with constitutive Rap1 activation (21). We also demonstrate that Rap1 activation by CTLA-4 antagonized TCR-dependent ERK activation, both in the presence and absence of CD28, and limited IL-2 production.…”

Section: Discussionsupporting

confidence: 89%

“…In the Rap1GAP1 and the AD10xRap1GAP1-transgenic animals, the ectopic expression of Rap1GAP1 did not grossly affect the thymocyte development. The absence of effects of Rap1 on T-cell development has also been reported for thymocytes that have heightened Rap1 activity from mice deficient in the endogenous T-cell Rap1GAP Spa-1 (21) and for the P14 TCRtransgenic mouse expressing constitutively active RapV12 (39). However, RapV12 expression enhanced positive selection in a low-affinity selection model, the HY-TCR-transgenic model (39).…”

Section: Discussionmentioning

confidence: 69%

“…During CD28 costimulation, Rap1 activation is inhibited (8,22,33) and ERK signaling is enhanced (8). Conversely, T lymphocytes lacking the Rap1GAP Spa-1 show constitutively elevated Rap1 activity, diminished ERK activation, and a decreased response to TCR stimulation (21). Models of T-cell anergy induced by lack of CD28 costimulation also show constitutively elevated Rap1 activity, diminished ERK activation, and decreased response to TCR stimulation (4).…”

mentioning

confidence: 99%

“…In contrast, Rap1 has been proposed to augment T-cell activation via its enhancement of integrin-dependent adhesion (22,39). Most models for the study of Rap1 function in T cells have examined constitutive Rap1 activation and, therefore, do not directly test the physiological role of Rap1 (21,39). To better address the function of Rap1 in T-cell activation, we expressed Rap1GAP1 in T cells.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Dillon

Carey

Wetzel

et al. 2005

Molecular and Cellular Biology

View full text Add to dashboard Cite

The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPaseactivating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.The activation of T cells requires antigen recognition through the T-cell receptor (TCR) and costimulation via the CD28 coreceptor, which binds the family of B7 ligands (B7-1 and B7-2) expressed on antigen-presenting cells (APCs) (35). Additional complexity comes with another coreceptor, CTLA-4, that also binds B7 and can antagonize the ability of CD28 to stimulate T-cell activation and interleukin 2 (IL-2) accumulation (25,27,28,42,44). Recent studies have suggested that inhibition of extracellular signal-regulated kinases (ERKs) may contribute to this action (6, 9, 38). ERKs are activated following costimulation by TCR/CD28 and are required for AP-1-dependent transcription of IL-2, a cytokine that is essential for T-cell proliferation (32, 46). Cross-linking anti-CTLA-4 antibodies (that activate CTLA-4) inhibit both ERK activation and IL-2 production following costimulation by TCR/CD28 (6, 9). The mechanism by which CTLA-4 inhibits ERK activation is not known.The small G protein Ras mediates TCR activation of ERKs (7). TCR stimulation triggers the activation of Ras via the Ras guanine nucleotide exchange factors (GEF) Cal DAG-GEF II (also called Ras-GRP1) (17) and SOS (47). Ras is a positive activator of the mitogen-activated protein (MAP) kinase kinase kinase Raf-1 that can phosphorylate and activate the MAP kinase kinase MEK, which, in turn, can activate ERK. Potential negative regulatory molecules are also activated by TCR stimulation. One of these is the small G protein Rap1 that, like Ras, can be inhibited by specific GTPase-activating proteins (Rap1GAPs). Rap1 is activated following stimulation of the TCR (1, 8) and, like Ras, is rapidly recruited to the plasma membrane upon activation (3). During CD28 costimulation, Rap1 activation is inhibited (8,22,33) and ERK signaling is enhanced (8). Conversely, T lymphocytes lacking the Rap1GAP Spa-1 show constitutively elevated Rap1 activity, diminished ERK activation, and a decreased response to TCR stimulation (21). ...

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 69%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Dillon

Carey

Wetzel

et al. 2005

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…The function of Rap1 as a negative regulator for T cell activation was confirmed by a knockout study of SPA-1, a principle Rap1 GTPase-activating protein, showing that accumulation of large amounts of active Rap1 correlated with T cell hyporesponsiveness and down-regulation of ERK activation (64). In our system, the levels of active Rap1 in orally tolerized T cells was higher, but only slightly, than those in control T cells (Fig.…”

Section: Discussionsupporting

confidence: 73%

Orally Tolerized T Cells Can Form Conjugates with APCs but Are Defective in Immunological Synapse Formation

Ise

Nakamura

Shimizu

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Oral tolerance is systemic immune hyporesponsiveness induced by the oral administration of soluble Ags. Hyporesponsiveness of Ag-specific CD4 T cells is responsible for this phenomenon. However, the molecular mechanisms underlying the hyporesponsive state of these T cells are not fully understood. In the present study, we investigated the ability of orally tolerized T cells to form conjugates with Ag-bearing APCs and to translocate TCR, protein kinase C-θ (PKC-θ), and lipid rafts into the interface between T cells and APCs. Orally tolerized T cells were prepared from the spleens of OVA-fed DO11.10 mice. Interestingly, the orally tolerized T cells did not show any impairment in the formation of conjugates with APCs. The conjugates were formed in a LFA-1-dependent manner. Upon antigenic stimulation, the tolerized T cells could indeed activate Rap1, which is critical for LFA-1 activation and thus cell adhesion. However, orally tolerized T cells showed defects in the translocation of TCR, PKC-θ, and lipid rafts into the interface between T cells and APCs. Translocation of TCR and PKC-θ to lipid raft fractions upon antigenic stimulation was also impaired in the tolerized T cells. Ag-induced activation of Vav, Rac1, and cdc42, which are essential for immunological synapse and raft aggregation, were down-regulated in orally tolerized T cells. These results demonstrate that orally tolerized T cells can respond to specific Ags in terms of conjugate formation but not with appropriate immunological synapse formation. This may account for the hyporesponsive state of orally tolerized T cells.

show abstract

Sustained T cell Rap1 signaling is protective in the collagen‐induced arthritis model of rheumatoid arthritis

Abreu¹,

Krausz²,

Dontje³

et al. 2010

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Defective activation of T cell receptorproximal signaling proteins, such as the small GTPase Rap1, is thought to contribute to the pathologic behavior of rheumatoid arthritis (RA) synovial T cells. This study was undertaken to determine whether maintaining Rap1 signaling in murine T cells modifies disease onset or severity in collagen-induced arthritis (CIA).Methods. CIA experiments were conducted using wild-type and RapV12-transgenic mice, which express an active mutant of Rap1 in the T cell compartment. Mice were assessed using macroscopic, microscopic, and radiologic measures, and serum levels of anticollagen antibodies were measured by enzyme-linked immunosorbent assay. Phenotypic and functional characterization of wild-type and RapV12-transgenic T cells under homeostatic conditions and during disease onset was performed by flow cytometry.Results. Disease incidence and severity, synovial infiltration, joint destruction, and anticollagen antibody production were significantly reduced in RapV12-transgenic mice. Although the numbers and percentages of CD3؉, CD4؉, and CD8؉ (naive, effector, and memory) T cells, Treg cells, and Th17 cells were equivalent in wild-type and RapV12-transgenic mice, a significant decrease in the percentage of tumor necrosis factor ␣-secreting CD8؉ T cells was observed in RapV12-transgenic mice during CIA. RapV12-transgenic T cells also inefficiently expressed inducible costimulator and CD40L costimulatory proteins involved in B cell immunoglobulin class switching.Conclusion. Our findings indicate that maintenance of T cell Rap1 signaling in murine T cells reduces disease incidence and severity in CIA, which are associated with specific defects in T cell effector function.

show abstract

Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Cited by 41 publications

References 35 publications

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Orally Tolerized T Cells Can Form Conjugates with APCs but Are Defective in Immunological Synapse Formation

Sustained T cell Rap1 signaling is protective in the collagen‐induced arthritis model of rheumatoid arthritis

Contact Info

Product

Resources

About