CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes

Camperio, Cristina; Muscolini, Michela; Volpe, Elisabetta; Mitri, Diletta Di; Mechelli, Rosella; Buscarinu, Maria Chiara; Ruggieri, Serena; Piccolella, Enza; Salvetti, Marco; Gasperini, Claudio; Battistini, Luca; Tuosto, Loretta

doi:10.1016/j.imlet.2013.12.020

Cited by 34 publications

(59 citation statements)

References 69 publications

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“…1E). Consistent with the role of RelA/NF-kB in regulating IL-8 gene transcription in CD4 + T cells (3,6), the overexpression of PIP5Ka (K182A) significantly inhibited IL-8 transcription (65%) induced by CD28 individual ligation (Fig. 1C).…”

Section: Cd28-dependent Signalssupporting

confidence: 78%

Phosphatidylinositol 4–Phosphate 5–Kinase α and Vav1 Mutual Cooperation in CD28-Mediated Actin Remodeling and Signaling Functions

Muscolini

Camperio

Porciello

et al. 2015

The Journal of Immunology

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Phosphatidylinositol 4,5–biphosphate (PIP2) is a cell membrane phosphoinositide crucial for cell signaling and activation. Indeed, PIP2 is a pivotal source for second messenger generation and controlling the activity of several proteins regulating cytoskeleton reorganization. Despite its critical role in T cell activation, the molecular mechanisms regulating PIP2 turnover remain largely unknown. In human primary CD4+ T lymphocytes, we have recently demonstrated that CD28 costimulatory receptor is crucial for regulating PIP2 turnover by allowing the recruitment and activation of the lipid kinase phosphatidylinositol 4–phosphate 5–kinase (PIP5Kα). We also identified PIP5Kα as a key modulator of CD28 costimulatory signals leading to the efficient T cell activation. In this study, we extend these data by demonstrating that PIP5Kα recruitment and activation is essential for CD28-mediated cytoskeleton rearrangement necessary for organizing a complete signaling compartment leading to downstream signaling functions. We also identified Vav1 as the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions.

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Section: Cd28-dependent Signalssupporting

confidence: 78%

Phosphatidylinositol 4–Phosphate 5–Kinase α and Vav1 Mutual Cooperation in CD28-Mediated Actin Remodeling and Signaling Functions

Muscolini

Camperio

Porciello

et al. 2015

The Journal of Immunology

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“…It transiently decreased the Tregs and increased IL-17A production in lymphoid organs [24-26]. In other chronic inflammatory states, increased IL-6 production by CD4 + non-regulatory T cells (non-Tregs) has been reported [27-29]. It is possible that the pro-inflammatory state observed in CA infants results from or causes reduced CD4 + cell numbers and/or function that in turn contribute to self-injurious inflammation in these infants.…”

Section: Introductionmentioning

confidence: 99%

Preterm cord blood CD4+ T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4+ T cells in bronchopulmonary dysplasia

et al. 2015

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Background Chorioamnionitis (CA) is associated with premature delivery and bronchopulmonary dysplasia (BPD). We hypothesize that preterm infants exposed to CA have reduced suppressive regulatory T cells (Treg) and increased non-regulatory T cell pro-inflammatory cytokines, increasing risk for BPD. Objective To evaluate cord blood CD4+ T cell regulatory phenotype and pro-inflammatory cytokine production in CA and BPD groups. Study Design Cord blood mononuclear cells from infants (GA ≤32 weeks), with or without placental histological evidence of CA (hChorio), were analyzed by flow cytometry. Clinical information was collected by retrospective chart review. Numbers of putative Treg (CD4+FoxP3+CD25+CD127Dim), CD4+ non-Tregs, and CD4+ T cell intracellular cytokine content following in vitro stimulation were compared with CA status and oxygen requirement at 36 weeks postmenstrual age. Result Absolute Treg numbers were not different in CA and non-CA exposed samples. However, the infants who developed BPD had a significant decrease in Treg and non-regulatory T cell numbers. Greater IL-6 production was observed in hCA group. Conclusion A pro-inflammatory CD4+ T cell status is noted in CA and BPD but the later disease is also associated with decrease in Tregs, suggesting that the development of BPD is marked by distinct inflammatory changes from those of CA exposed infants.

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“…CD28 is the crucial determinant of T lymphocyte activation, as it promotes the cytoskeletal rearrangement events required for relocalization of receptors, lipid raft accumulation, and organization of a signaling compartment at the IS (9,14). CD28 regulates the remodeling of the actin cytoskeleton independently of TCR signals (33,47,48), thus acting as an amplifier of both early TCR signaling (10,12) and autonomous signaling mediator (49,50). CD28 also recruits FLNA, which in turn cooperates with Vav1 in mediating the actin polymerization pathway to induce lipid raft accumulation at the IS (14).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4-Phosphate 5-Kinase β Controls Recruitment of Lipid Rafts into the Immunological Synapse

Kallikourdis

Trovato

Roselli

et al. 2016

The Journal of Immunology

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Phosphatidylinositol 4,5-biphosphate (PIP2) is critical for T lymphocyte activation serving as a substrate for the generation of second messengers and the remodeling of actin cytoskeleton necessary for the clustering of lipid rafts, TCR, and costimulatory receptors toward the T:APC interface. Spatiotemporal analysis of PIP2 synthesis in T lymphocytes suggested that distinct isoforms of the main PIP2-generating enzyme, phosphatidylinositol 4-phosphate 5-kinase (PIP5K), play a differential role on the basis of their distinct localization. In this study, we analyze the contribution of PIP5Kβ to T cell activation and show that CD28 induces the recruitment of PIP5Kβ to the immunological synapse, where it regulates filamin A and lipid raft accumulation, as well as T cell activation, in a nonredundant manner. Finally, we found that Vav1 and the C-terminal 83 aa of PIP5Kβ are pivotal for the PIP5Kβ regulatory functions in response to CD28 stimulation.

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CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes

Cited by 34 publications

References 69 publications

Phosphatidylinositol 4–Phosphate 5–Kinase α and Vav1 Mutual Cooperation in CD28-Mediated Actin Remodeling and Signaling Functions

Phosphatidylinositol 4–Phosphate 5–Kinase α and Vav1 Mutual Cooperation in CD28-Mediated Actin Remodeling and Signaling Functions

Preterm cord blood CD4+ T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4+ T cells in bronchopulmonary dysplasia

Phosphatidylinositol 4-Phosphate 5-Kinase β Controls Recruitment of Lipid Rafts into the Immunological Synapse

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