B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4

Mandelbrot, Didier A.; Oosterwegel, Mariëtte A.; Shimizu, Koïchi; Yamada, Akira; Freeman, Gordon J.; Mitchell, Richard N.; Sayegh, M. H.; Sharpe, Arlene H.

doi:10.1172/jci11710

Cited by 77 publications

(69 citation statements)

References 25 publications

(16 reference statements)

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“…Lastly, recent studies by Mandelbrot and colleagues and Yamada and colleagues suggest that a third receptor exists for the B7 ligands (86,87). Together with our studies, these findings suggest that not only may CD28 have a differential role in the direct vs. indirect pathways, but that CD28-B7 blockade may effect other potentially important pathways.…”

Section: Discussionsupporting

confidence: 84%

Inability to Induce Tolerance Through Direct Antigen Presentation

Rulifson

Szot

Palmer

et al. 2002

American Journal of Transplantation

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Both the direct and indirect antigen presentation pathways are important mechanisms for T cell-mediated allograft rejection. Studies using knockout mice and monoclonal antibodies have demonstrated that CD4π T cells are both necessary and sufficient for the rejection of allogeneic tissues, including skin, heart, and islet. Furthermore, combined blockade of the CD28/B7 and CD154/CD40 costimulatory pathways induces tolerance in multiple CD4π T-cell dependent allograft models. In this study, we addressed the T-cell requirement for costimulation in direct antigen presentation. We demonstrated that class II-specific alloreactive Tcell receptor transgenic T cells were sufficient to mediate allograft rejection independent of costimulatory blockade. Analysis of the costimulatory capacity of different antigen presenting cell (APC) populations demonstrated that APCs resident within the donor skin, Langerhans cells, are potent stimulators not requiring CD28-or CD154-dependent costimulation for direct major histocompatibility complex (MHC) antigen presentation. These results complement previous work examining the role of costimulation on CD8π T cells, supporting a model in which the effectiveness of costimulatory blockade in the setting of transplantation may be selective for the indirect pathway of MHC alloantigen presentation.

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Section: Discussionsupporting

confidence: 84%

Inability to Induce Tolerance Through Direct Antigen Presentation

Rulifson

Szot

Palmer

et al. 2002

American Journal of Transplantation

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“…We asked whether the lack of suppressive capacity of GFP ϩ Foxp3 Ϫ sf Tregs could be explained by changes in the protein expression levels of known suppression-related molecules such as CTLA-4 or GITR. CTLA-4 has been suggested to be an essential molecule for Treg-mediated suppression, and the knockout of CTLA-4 results in a phenotype comparable to the sf mouse mutant, suggesting overlapping functions of Foxp3 and CTLA-4 (45)(46)(47). GITR interaction with its ligand GITR-L on accessory cells has been linked to induction of regulatory properties and proliferation of plasmacytoid dendritic cells (48).…”

Section: Discussionmentioning

confidence: 99%

Nonfunctional Regulatory T Cells and Defective Control of Th2 Cytokine Production in Natural Scurfy Mutant Mice

Lahl

Mayer

Bopp

et al. 2009

The Journal of Immunology

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Foxp3+ regulatory T cells (Tregs) are crucial for preventing autoimmunity. We have demonstrated that depletion of Foxp3+ Tregs results in the development of a scurfy-like disease, indicating that Foxp3− effector T cells are sufficient to induce autoimmunity. It has been postulated that nonfunctional Tregs carrying potentially self-reactive T cell receptors may contribute to scurfy (sf) pathogenesis due to enhanced recognition of self. Those cells, however, could not be identified in sf mutants due to the lack of Foxp3 protein expression. To address this issue, we crossed the natural sf mouse mutant with bacterial artificial chromosome transgenic DEREG (depletion of regulatory T cells) mice. Since DEREG mice express GFP under the control of an additional Foxp3 promoter, those crossings allowed proving the existence of “would-be” Tregs, which are characterized by GFP expression in the absence of functional Foxp3. Sf Tregs lost their in vitro suppressive capacity. This correlated with a substantial reduction of intracellular cAMP levels, whereas surface expression of Treg markers was unaffected. Both GFP+ and GFP− sf cells produced high amounts of Th2-type cytokines, reflected also by enhanced Gata-3 expression, when tested in vitro. Nevertheless, sf Tregs could be induced in vitro, although with lower efficiency than DEREG Tregs. Transfer of GFP+ sf Tregs, in contrast to GFP− sf T cells, into RAG1-deficient animals did not cause the sf phenotype. Taken together, natural and induced Tregs develop in the absence of Foxp3 in sf mice, which lack both suppressive activity and autoreactive potential, but rather display a Th2-biased phenotype.

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“…However, consistent with previous reports (20,21), we have found that SAg-mediated negative selection proceeds normally in CD28 KO mice. Recently, CTLA-4 has been implicated in negative selection (22) and evidence to suggest the existence of other, yet undefined, B7 receptors has been obtained in studies of CD28-CTLA-4 DKO (23,24). These findings suggested that, although negative selection is intact in CD28 KO mice, defects in negative selection might be observed in the absence of both B7-1 and B7-2.…”

Section: Figurementioning

confidence: 99%

CD40 Ligand Functions Non-Cell Autonomously to Promote Deletion of Self-Reactive Thymocytes

Williams

Sharrow

Adams

et al. 2002

The Journal of Immunology

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CD40 ligand (CD40L)-deficient mice have been shown to have a defect in negative selection of self-reactive T cells during thymic development. However, the mechanism by which CD40L promotes deletion of autoreactive thymocytes has not yet been elucidated. We have studied negative selection in response to endogenous superantigens in CD40L-deficient mice and, consistent with previous reports, have found a defect in negative selection in these mice. To test the requirement for expression of CD40L on T cells undergoing negative selection, we have generated chimeric mice in which CD40L wild-type and CD40L-deficient thymocytes coexist. We find that both CD40L wild-type and CD40L-deficient thymocytes undergo equivalent and efficient negative selection when these populations coexist in chimeric mice. These results indicate that CD40L can function in a non-cell-autonomous manner during negative selection. Deletion of superantigen-reactive thymocytes was normal in B7-1/B7-2 double-knockout mice, indicating that CD40-CD40L-dependent negative selection is not solely mediated by B7 up-regulation and facilitation of B7-dependent T cell signaling. Finally, although the absence of CD40-CD40L interactions impairs negative selection of autoreactive CD4+ and CD8+ cells during thymic development, we find that self-reactive T cells are deleted in the mature CD4+ population through a CD40L-independent pathway.

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B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4

Cited by 77 publications

References 25 publications

Inability to Induce Tolerance Through Direct Antigen Presentation

Inability to Induce Tolerance Through Direct Antigen Presentation

Nonfunctional Regulatory T Cells and Defective Control of Th2 Cytokine Production in Natural Scurfy Mutant Mice

CD40 Ligand Functions Non-Cell Autonomously to Promote Deletion of Self-Reactive Thymocytes

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