Ligation of CD28 by Its Natural Ligand CD86 in the Absence of TCR Stimulation Induces Lipid Raft Polarization in Human CD4 T Cells

Kovacs, Birgit; Parry, Richard V.; Ma, Zhengyu; Fan, Emily Y.; Shivers, Debra K.; Freiberg, Benjamin A.; Thomas, Anna; Rutherford, Robert; Rumbley, Catherine A.; Riley, James L.; Finkel, Terri H.

doi:10.4049/jimmunol.175.12.7848

Cited by 32 publications

(33 citation statements)

References 38 publications

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“…As such, many costimulatory ligands have limited activity as soluble proteins due to inefficient signal transduction (40,41,47). Although agonistic Abs against costimulatory receptors are effective in delivering immunological signals, there is evidence suggesting that signals delivered by Abs may quantitatively and qualitatively differ from signals transduced by natural ligands (37)(38)(39). In an attempt to use signaling via 4-1BB as an alternative to CD28-mediated costimulation for the expansion of Treg cells, we constructed a novel form of 4-1BBL chimeric with SA (SA-4-1BBL) that functions as a soluble protein.…”

Section: Generation Of a Chimeric 4-1bbl Molecule Having Potent Costimentioning

confidence: 99%

“…Under physiological conditions, costimulatory receptors are cross-linked by cell membrane-bound ligands (38,46). As such, many costimulatory ligands have limited activity as soluble proteins due to inefficient signal transduction (40,41,47).…”

Section: Generation Of a Chimeric 4-1bbl Molecule Having Potent Costimentioning

confidence: 99%

“…We chose to use 4-1BBL, instead of 4-1BB Ab, for stimulation because signals generated by agonistic Abs may qualitatively and quantitatively differ from those delivered by natural ligands (37)(38)(39). Inasmuch as native 4-1BBL does not have costimulatory function as a soluble protein (40,41), we generated the novel form SA-4-1BBL by fusing the extracellular domains of 4-1BBL to a modified form of core streptavidin (SA), thereby allowing for the existence of oligomeric 4-1BBL proteins capable of cross-linking 4-1BB receptors.…”

Section: N Aturally Occurring Cd4mentioning

confidence: 99%

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Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Elpek

Yolcu

Franke

et al. 2007

The Journal of Immunology

126

143

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Naturally occurring CD4+CD25+FoxP3+ T regulatory (Treg) cells require three distinct signals transduced via TCR, CD28, and IL-2R for their development and maintenance. These requirements served as the basis for several recently developed ex vivo expansion protocols that relied on the use of solid support-bound Abs to CD3 and CD28 in the presence of high dose IL-2. We report in this study that Treg cells up-regulate the expression of inducible costimulatory receptor 4-1BB in response to IL-2, and stimulation using this receptor via a novel form of 4-1BB ligand (4-1BBL) fused to a modified form of core streptavidin (SA-4-1BBL) was effective in expanding these cells up to 110-fold within 3 wk. Expanded cells up-regulated CD25, 4-1BB, and membranous TGF-β, suppressed T cell proliferation, and prevented the rejection of allogeneic islets upon adoptive transfer into graft recipients. Importantly, SA-4-1BBL rendered CD4+CD25− T effector cells refractive to suppression by Treg cells. This dual function of signaling via 4-1BB, vis-à-vis Treg cell expansion and licensing T effector cells resistant to Treg cell suppression, as well as the up-regulation of 4-1BB by IL-2 may serve as important regulatory mechanisms for immune homeostasis following antigenic challenge. Stimulation using a soluble form of SA-4-1BBL represents a novel approach to expand Treg cells with potential therapeutic applications in autoimmunity and transplantation.

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Section: Generation Of a Chimeric 4-1bbl Molecule Having Potent Costimentioning

confidence: 99%

Section: Generation Of a Chimeric 4-1bbl Molecule Having Potent Costimentioning

confidence: 99%

Section: N Aturally Occurring Cd4mentioning

confidence: 99%

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Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Elpek

Yolcu

Franke

et al. 2007

The Journal of Immunology

126

143

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“…MIR1 downregulates all human class I MHC, gamma interferon receptor (IFN-␥R), and CD1d, whereas MIR2 downregulates a subset of MHC-I molecules (HLA-A and HLA-B), IFN-␥R, CD1d, platelet endothelial cell adhesion molecule 1 (PECAM-l), intercellular adhesion molecule 1 (ICAM-l), B7.2, bone marrow stromal cell antigen 2 (BST-2), syntaxin 4, and activated leukocyte cell adhesion molecule (ALCAM; CD166) (2,5,6,15,16,21,23,24,30). Most of these substrates are known to reside in, or upon activation are recruited to, lipid rafts (8,18,32,35), microdomains of the plasma membrane thought to be important for a wide range of signal transduction events, including T cell and B cell activation.Posttranslational modifications can target proteins to specific regions of the plasma membrane. Palmitoylation is a type of fatty acid modification in which palmitic acid is attached to sulfur atoms of cysteine residues, making polypeptides more hydrophobic.…”

mentioning

confidence: 99%

Palmitoylation of MIR2 Is Required for Its Function

Anania

Coscoy

2011

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) encodes two RING finger E3 ubiquitin ligases (MIR1 and MIR2) that mediate ubiquitination and degradation of cellular proteins important for the establishment of an efficient antiviral immune response. MIR1 and MIR2 share 30% sequence identity; however, their substrate preferences are varied. MIR1 has been shown to primarily downregulate major histocompatibility complex class I (MHC-I), whereas MIR2 can downregulate a wide range of cell surface proteins. Many of the MIR substrates are thought to be present in lipid raft microdomains, a subregion of the plasma membrane known to be important for a wide range of signal transduction events. Palmitoylation is a posttranslational modification that increases recruitment of transmembrane proteins to lipid rafts. In this study, we investigated the importance of palmitoylation for MIR function. We present evidence that MIR2-mediated downregulation of MHC-I and platelet endothelial cell adhesion molecule 1 (PECAM-1) but not other substrates is inhibited in the presence of the drug 2-bromohexadecanoic acid (2-Br), a chemical inhibitor of palmitoylation. Biochemical analysis indicates that MIR2 is directly palmitoylated on cysteine 146. Mutation of this cysteine to a phenylalanine prevents MIR2 palmitoylation and blocks the ability of MIR2 to downregulate MHC-I and PECAM-I but not B7.2 and intercellular adhesion molecule 1 (ICAM-I), consistent with the phenotype observed after 2-Br treatment. Unpalmitoylated MIR2 does not interact with MHC-I and is thus unable to ubiquitinate and downregulate MHC-I from the cell surface. Furthermore, we observed that MIR2 is palmitoylated in vivo during lytic infection. Palmitoylation may act to regulate MIR2 function and localization during viral infection by allowing MIR2 to properly interact with and downregulate multiple substrates known to play an important role in the host immune response.Kaposi's sarcoma-associated herpesvirus (KSHV) is a large, double-stranded DNA gamma-2 herpesvirus that is the causative agent of Kaposi's sarcoma as well as two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castleman's disease (11,34). KSHV is a persistent virus that devotes a large fraction of its genome to encoding proteins involved in immune evasion (4). Two such viral products are the Modulator of Immune Responses 1 and 2 (MIR1 and MIR2). These proteins are transmembrane RING finger E3 ligases that cause ubiquitination and downregulation of major histocompatibility complex class I (MHC-I) molecules and other plasma membrane proteins involved in immune responses (reviewed in reference 20). The MIR proteins are homologous to the membrane-associated RING-CH protein family (MARCH) of E3 ubiquitin ligases (20) found in a broad range of mammals.Ubiquitination is a conserved and highly regulated process in all eukaryotic species (reviewed in references 14 and 27). Through an ATP hydrolysis reaction, the C-terminal glycine residue of ubiquitin forms a thioester bond with the cataly...

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“…Our rationale was that sustained heating seems to be able to replace at least some of the function of costimulation through CD28, which is known to be mediated through cholesterol-dependant nanodomain reorganization at the cell surface. 35 In addition, Brameshuber et al demonstrated that fever-range heat induced raft-destabilization/reorganization in living cells. 36 Could the co-stimulatory cues (e.g.…”

Section: Cd4c T Cells From (A) Wild Type and (B) Cd28mentioning

confidence: 99%

A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation

et al. 2015

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Abbreviations: APC, antigen-presenting cell; CD28, cluster of differentiation 28; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CTxB, cholera toxin B subunit; Ct, cycle threshold; ELISA, enzyme-linked immunosorbant assay; EtOH, ethanol; FITC, fluoroisothiocyanate; GM1, monosialotetrahexosylganglioside; IDEAS, imagestream data exploration and analysis software; IL-2, interleukin 2; LA, latrunculin A;MbCD, methyl-b-cyclodextrin; PD-1, Programmed cell death-1; PMA, phorbol 12-myristate 13-acetate; pMHC, peptide-major histocompatibility complexes; qRT-PCR, quantitative reverse transcription polymerase chain reaction; TCR, T cell receptor; TDI, time delay integration; TMA-DPH, trimethylammonium diphenylhexatriene; WBH, whole body hyperthermia.Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4C T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4C T cells to become more quickly and easily activated during times of infection during fever.

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Ligation of CD28 by Its Natural Ligand CD86 in the Absence of TCR Stimulation Induces Lipid Raft Polarization in Human CD4 T Cells

Cited by 32 publications

References 38 publications

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Palmitoylation of MIR2 Is Required for Its Function

A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation

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Ligation of CD28 by Its Natural Ligand CD86 in the Absence of TCR Stimulation Induces Lipid Raft Polarization in Human CD4 T Cells

Cited by 32 publications

References 38 publications

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling

Palmitoylation of MIR2 Is Required for Its Function

A role for the thermal environment in defining co-stimulation requirements for CD4+T cell activation

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A role for the thermal environment in defining co-stimulation requirements for CD4⁺T cell activation