A Blocking Anti-CD28-Specific Antibody Induces Long-Term Heart Allograft Survival by Suppression of the PKCθ-JNK Signal Pathway

Jang, Mei Shiang; Fan, Ping; Erickson, Laurie; Fisniku, Ogert; Crews, Gladys; Wynn, Carmen; Hong, Ickpyo; Tamura, Kouichi; Kobayashi, Masakazu; Jiang, Hongsi

doi:10.1097/tp.0b013e31816846f6

Cited by 22 publications

(19 citation statements)

References 24 publications

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“…This conclusion is consistent with the well-established role of PKCθ as a T cell survival factor (Barouch-Bentov, et al, 2005; Manicassamy, Gupta, et al, 2006; Saibil, Jones, et al, 2007) that regulates pro- and anti-apoptotic Bcl2 family members in opposite ways, respectively. Of interest, a blocking (antagonistic) anti-CD28 antibody was found to enable long-term survival of heart allografts across a complete MHC mismatch, and this effect was associated with impaired early TCR signaling events, including PKCθ activation (Jang, et al, 2008). …”

Section: The Differential Role Of Pkcθ In Immune Responsesmentioning

confidence: 99%

“…Second, Prkcq −/− T cells display an anergic phenotype upon antigen challenge, similar to that of Cd28 −/− mice (Berg-Brown, et al, 2004). And, third, a blocking anti-CD28-specific antibody was reported to induce long-term heart allograft survival by suppressing the PKCθ-JNK signaling pathway (Jang, et al, 2008). Given the less severe inhibitory effect of Prkcq deletion on the Ca 2+ -NFAT signaling pathway relative to the AP-1 and NF-κB pathways, it is therefore conceivable that in the absence of PKCθ, there would be sufficient residual NFAT activation but nearly absent AP-1 and NF-κB activation, conditions that would favor the induction of T cell anergy (Heissmeyer, et al, 2004).…”

Section: Pkcθ Cd28 Costimulation and T Cell Anergymentioning

confidence: 99%

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The Yin and Yang of Protein Kinase C-theta (PKCθ)

Zhang

Kong

Altman

2013

Advances in Pharmacology

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Protein kinase C-θ (PKCθ) is a PKC family member expressed predominantly in T lymphocytes, and extensive studies addressing its function have been conducted. PKCθ is the only T cell-expressed PKC that localizes selectively to the center of the immunological synapse (IS) following conventional T cell antigen stimulation, and this unique localization is essential for PKCθ-mediated downstream signaling. While playing a minor role in T cell development, early in vitro studies relying, among others, on the use of PKCθ-deficient (Prkcq−/−) T cells revealed that PKCθ is required for the activation and proliferation of mature T cells, reflecting its importance in activating the transcription factors NF-κB, AP-1 and NFAT, as well as for the survival of activated T cells. Upon subsequent analysis of in vivo immune responses in Prkcq−/− mice, it became clear that PKCθ has a selective role in the immune system: It is required for experimental Th2 and Th17-mediated allergic and autoimmune diseases, respectively, and for alloimmune responses, but is dispensable for protective responses against pathogens and for graft-vs.-leukemia responses. Surprisingly, PKCθ was recently found to be excluded from the IS of regulatory T cells (Tregs) and to negatively regulate their suppressive function. These attributes of PKCθ make it an attractive target for catalytic or allosteric inhibitors that are expected to selectively suppress harmful inflammatory and alloimmune responses without interfering with beneficial immunity to infections. Early progress in developing such drugs is being made, but additional studies on the role of PKCθ in the human immune system are urgently needed.

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Section: The Differential Role Of Pkcθ In Immune Responsesmentioning

confidence: 99%

Section: Pkcθ Cd28 Costimulation and T Cell Anergymentioning

confidence: 99%

The Yin and Yang of Protein Kinase C-theta (PKCθ)

Zhang

Kong

Altman

2013

Advances in Pharmacology

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“…Engagement of the TCR in Cd28 – / – T cells results in altered, diffuse pattern of distribution of PKCθ and LFA-1 at the IS, suggesting an essential role for CD28 in the initiation and stabilization of the mature IS (Huang et al, 2002; Sanchez-Lockhart et al, 2004). Furthermore, in vivo blocking of CD28 impairs the activity of effector molecules, including PKCθ (Jang et al, 2008), and inhibits T cell-dependent immune responses (Linsley and Nadler, 2009). CD28 engagement promotes a cytoskeleton-dependent recruitment of cell surface receptors (Wulfing and Davis, 1998) and signaling molecules-containing lipid rafts that support building the IS and contribute to signal transduction from IS-residing receptors (Dustin and Shaw, 1999; Viola et al, 1999).…”

Section: Cd28 and The Ismentioning

confidence: 99%

PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors

Isakov

2012

Front. Immun.

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Protein kinase C-theta (PKCθ) is a key enzyme in T lymphocytes, where it plays an important role in signal transduction downstream of the activated T cell antigen receptor (TCR) and the CD28 costimulatory receptor. Interest in PKCθ as a potential drug target has increased following recent findings that PKCθ is essential for harmful inflammatory responses mediated by Th2 (allergies) and Th17 (autoimmunity) cells as well as for graft-versus-host disease (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral immunity and graft-versus-leukemia (GvL) response. TCR/CD28 engagement triggers the translocation of the cytosolic PKCθ to the plasma membrane (PM), where it localizes at the center of the immunological synapse (IS), which forms at the contact site between an antigen-specific T cell and antigen-presenting cells (APC). However, the molecular basis for this unique localization, and whether it is required for its proper function have remained unresolved issues until recently. Our recent study resolved these questions by demonstrating that the unique V3 (hinge) domain of PKCθ and, more specifically, a proline-rich motif within this domain, is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism involving Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKCθ with CD28 is essential not only for IS localization, but also for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT, which are essential for productive T cell activation. Hence, interference with formation of the PKCθ-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKCθ inhibitors. An additional recent study demonstrated that TCR triggering activates the germinal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKCθ, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKCθ in human T cells, is likely to facilitate the development of PKCθ-based therapeutic modalities for T cell-mediated diseases.

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“…52,53 Conversely, their other crucial role is to block the development of several autoimmune diseases or to induce donor-specific tolerance to allografts by abrogation of CD28/B7 signals. [47][48][49][50] Through these apparently opposing roles of CD80 and CD86, PU.1 can be targeted for clinical treatment due to its inducible and inhibitory effects.…”

Section: Role Of Pu1 In the Expression Of Cd80 And Cd86 2219mentioning

confidence: 99%

Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

Kanada

Nishiyama

Nakano

et al. 2011

Blood

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In this study, we investigated the role of a transcription factor, PU.1, in the regulation of CD80 and CD86 expression in dendritic cells (DCs). A chromatin immunoprecipitation assay revealed that PU.1 is constitutively bound to the CD80 and CD86 promoters in bone marrow-derived DCs. In addition, co-expression of PU.1 resulted in the transactivation of the CD80 and CD86 promoters in a reporter assay. The binding of PU.1 to cis-enhancing regions was confirmed by electromobility gel-shift assay. As expected, inhibition of PU.1 expression by short interfering RNA (siRNA) in bone marrow-derived DCs resulted in marked down-regulation of CD80 and CD86 expression. Moreover, overexpression of PU.1 in murine bone marrow-derived lineage-negative cells induced the expression of CD80 and CD86 in the absence of monocyte/ DC-related growth factors and/or cytokines. Based on these results, we conclude that PU.1 is a critical factor for the expression of CD80 and CD86. We also found that subcutaneous injection of PU.1 siRNA or topical application of a cream-emulsified PU.1 siRNA efficiently inhibited murine contact hypersensitivity. Our results suggest that PU.1 is a potential target for the treatment of immune-related diseases. (Blood. 2011; 117(7):2211-2222) IntroductionT-cell initiation requires 2 signals from antigen-presenting cells (APCs). The first signal comes from ligation of the T-cell receptor and the major histocompatibility complex (MHC)/antigen presented on the surface of APCs, and the second signal is via additional costimulatory molecules, including the interaction between the CD28 family on T cells and B7, eg, CD80 (B7-1) and CD86 (B7-2), expressed on the APC. 1-3 CD80 and CD86 are members of the immunoglobulin supergene family encoded by separate genes, and are expressed on dendritic cells (DCs) or up-regulated on activated macrophages/monocytes, B cells, and activated T cells. 1-6 CD80 or CD86 can provide costimulatory signals by engaging CD28 or CTLA4 (cytotoxic T-lymphocyte antigen 4; CD152) on T cells. The engagement of CD28 with CD80 or CD86 leads to multiple effects on the immune response, including T-cell activation and differentiation and tissue migration. [7][8][9] In contrast to CD28, the outcome of CTLA4 engagement on T cells is to suppress proliferation by transmitting an inhibitory signal. 10 In addition, a subset of T cells with potent immunoregulatory properties, CD4 ϩ CD25 ϩ regulatory T cells, constitutively expresses CTLA4. 11,12 Thus, interactions between CTLA4 and CD80 or CD86 provides an immunosuppressive function in modulating T-cell proliferation and plays a role in immune tolerance. Based on these observations, the regulated expression of costimulatory molecules is critical for immune function. Therefore, revealing the molecular mechanisms of gene expression of costimulatory molecules is essential for an understanding of the regulation of T cell-mediated immune responses.Despite the importance of CD80 and CD86, the critical transcription factor for gene expression of CD80 or CD86 is sti...

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A Blocking Anti-CD28-Specific Antibody Induces Long-Term Heart Allograft Survival by Suppression of the PKCθ-JNK Signal Pathway

Cited by 22 publications

References 24 publications

The Yin and Yang of Protein Kinase C-theta (PKCθ)

The Yin and Yang of Protein Kinase C-theta (PKCθ)

PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors

Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

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