Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence

Wasem, Christoph; Arnold, Diana; Saurer, Leslie; Corazza, Nadia; Jakob, Sabine; Herren, Simon; Vallan, Claudio; Mueller, Christoph; Brunner, Thomas

doi:10.1172/jci16344

Cited by 17 publications

(14 citation statements)

References 53 publications

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“…2). This observation is in contrast to data reported for other PKC inhibitors (Geiselhart et al, 1996;Han et al, 2000;Wasem et al, 2003; data not shown), indicating the improved target selectivity of AEB071.…”

Section: Aeb071 Is a Potent And Highly Selective Pan-pkccontrasting

confidence: 99%

The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation

Evenou¹,

Wagner²,

Zenke³

et al. 2009

J Pharmacol Exp Ther

144

127

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There is a pressing need for immunosuppressants with an improved safety profile. The search for novel approaches to blocking T-cell activation led to the development of the selective protein kinase C (PKC) inhibitor AEB071 (sotrastaurin). In cell-free kinase assays AEB071 inhibited PKC, with K i values in the subnanomolar to low nanomolar range. Upon T-cell stimulation, AEB071 markedly inhibited in situ PKC catalytic activity and selectively affected both the canonical nuclear factor-B and nuclear factor of activated T cells (but not activator protein-1) transactivation pathways. In primary human and mouse T cells, AEB071 treatment effectively abrogated at low nanomolar concentration markers of early T-cell activation, such as interleukin-2 secretion and CD25 expression. Accordingly, the CD3/CD28 antibody-and alloantigen-induced T-cell proliferation responses were potently inhibited by AEB071 in the absence of nonspecific antiproliferative effects. Unlike former PKC inhibitors, AEB071 did not enhance apoptosis of murine T-cell blasts in a model of activation-induced cell death. Furthermore, AEB071 markedly inhibited lymphocyte function-associated antigen-1-mediated T-cell adhesion at nanomolar concentrations. The mode of action of AEB071 is different from that of calcineurin inhibitors, and AEB071 and cyclosporine A seem to have complementary effects on T-cell signaling pathways.Phosphorylation of serine, threonine, and tyrosine residues is a primary mechanism for regulating protein function in eukaryotic cells. Protein kinases, the enzymes that catalyze these reactions, regulate essentially all cellular processes and have thus emerged as therapeutic targets for many human diseases. However, nearly all protein kinase inhibitors target the ATP binding site. For this reason, design of inhibitors that selectively target even a subset of the approximately 570 related human protein kinase domains continues to be a daunting challenge. Nevertheless, small-molecule inhibitors of Abelson tyrosine kinase and epidermal growth factor receptor have been recently developed into clinically useful anticancer drugs (for review, see Medinger and Drevs, 2005).The protein kinase C (PKC) family of serine/threonine kinases plays a central role in the adaptive immune system. PKC can be grouped into three categories according to the

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Section: Aeb071 Is a Potent And Highly Selective Pan-pkccontrasting

confidence: 99%

The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation

Evenou¹,

Wagner²,

Zenke³

et al. 2009

J Pharmacol Exp Ther

144

127

View full text Add to dashboard Cite

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“…Interestingly, it has been recently reported that sensitize CD8 þ T cells for death during LCMV infection with bisindolylmaleimide VIII impairs cytotoxicity and viral clearance. 29 Thus, the consequence of the absence of armed effector cells in Mes LNs will be an inadequate 'immune barrier' unable to contain the virus inside the reservoirs and contribute to immune incompetence during SIV infection. It has been reported a decade ago that PBMC of HIVinfected individuals overexpress TGF-b.…”

Section: Discussionmentioning

confidence: 99%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

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“…Murine T cell blasts were pre-incubated with pharmacological inhibitors as indicated for 30 min, and then stimulated or not with plate-bound anti-CD3 or PMA for 6 h. Cells were harvested, total RNA was isolated and FasL expression was analyzed as described previously. 40 Generation and transfection of Fas-negative Jurkat cells (JOM-2). Fas-deficient Jurkat cells have been generated by treating Jurkat cells for 4-6 weeks using increasing concentrations of recombinant FasL (starting from 10 ng/ml up to 2000 ng/ml, Alexis).…”

Section: Degranulation Of Cytotoxic Granule Proteins D Kassahn Et Almentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

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Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4 þ and CD8 þ T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activationinduced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

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Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence

Cited by 17 publications

References 53 publications

The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation

The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

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