Analysis of the Cd40 and Cd28 Pathways on Alloimmune Responses by Cd4+ T Cells in Vivo1

Bingaman, Adam W.; Ha, Jongwon; Durham, Megan M.; Waitze, Seung Yeun; Tucker-Burden, Carol; Cowan, Shannon R.; Pearson, Thomas C.; Larsen, Christian

doi:10.1097/00007890-200110150-00018

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…Our results also provide further evidence for functional inhibition of alloantigen-reactive cells following CTLA4Ig administration in vivo. Consistent with findings by other investigators (9,29,30) IFN-c production by CD4 + T cells from CTLA4Ig-treated recipients was almost completely suppressed. The finding that the antigen-specific TCR-tg CD4 + T cells in transplanted mice treated with CTLA4Ig retained a naive phenotype supports previous observations that naive T cells require CD28 costimulation to become activated (26).…”

Section: Discussionsupporting

confidence: 92%

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Sandner

Salama

Houser

et al. 2003

American Journal of Transplantation

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We have developed an adoptive transfer model system to visualize the dynamics of alloantigen-specific CD4 + T-cell activation in vivo. Using TCR-transgenic (tg) mice reactive to I-A bm12 , we studied the clonal expansion and differentiation of alloreactive T cells by tracking the fate of adoptively transferred TCR-tg CD4 + T cells in syngeneic mice transplanted with skin grafts expressing I-A bm12 . Following transplantation, alloantigen-specific TCR-tg CD4 + T-cell expansion was observed initially in the draining lymph nodes followed by the spleen. TCR-tg CD4 + T cells up-regulated CD69 and CD25 expression, developed an effector/memory surface phenotype and produced IFN-c in response to alloantigen ex vivo. Furthermore, we validate the model system as a means for studying the effects of tolerogenic regimens on alloreactive CD4 + T cells, demonstrating that CTLA4Ig inhibits alloantigen-dependent clonal expansion and effector function of TCR-tg CD4 + T cells in vivo. We describe the first model for tracking alloreactive CD4 + T-cell activation in vivo. It provides a powerful tool for studying CD4 + T-cell mediated alloimmune responses and mechanisms of tolerance induction in vivo.

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Section: Discussionsupporting

confidence: 92%

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Sandner

Salama

Houser

et al. 2003

American Journal of Transplantation

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“…To test this hypothesis, we injected either WT or PTEN⌬T mice (B6 background) with allogeneic (BALB/c) splenocytes in the footpad and enumerated cells in the draining popliteal lymph node 72 h later. Consistent with prior reports, the ϳ8-fold expansion observed in response to alloantigen immunization is almost completely dependent on CD28 signals, being blocked by treatment of mice with CTLA4Ig (21). In contrast, the expansion/accumulation of PTEN-deficient CD4 ϩ T cells is virtually unaffected by a lack of CD28 signals (Fig.…”

Section: Cd4 ϩ T Cells That Lack Pten Have a Diminished Requirement Fsupporting

confidence: 91%

Cutting Edge: T Cell Requirement for CD28 Costimulation Is Due to Negative Regulation of TCR Signals by PTEN

Buckler¹,

Walsh²,

Porrett³

et al. 2006

The Journal of Immunology

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Recent studies suggest that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in the maintenance of self-tolerance. Using T cell-specific PTEN knockout mice (PTENΔT), we have identified a novel mechanism by which PTEN regulates T cell tolerance. We found that TCR stimulation alone, without CD28 costimulation, is sufficient to induce hyperactivation of the PI3K pathway, which leads to enhanced IL-2 production by naive PTENΔT T cells. Importantly, as a result of this increased response to TCR stimulation, PTENΔT CD4+ T cells no longer require CD28 costimulation for in vitro or in vivo expansion. In fact, unlike wild-type T cells, PTENΔT CD4+ T cells are not anergized by delivery of TCR stimulation alone. These data suggest that by negatively regulating TCR signals, PTEN imposes a requirement for CD28 costimulation, thus defining a novel mechanism for its role in self-tolerance.

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“…Thus, the blockade of CD154 on regulatory T cells acts as a positive feedback mechanism in that it blocks DC activation and provides an environment that supports and enhances the suppressive function of regulatory T cells. In general, it seems that regulatory T-cell function may be enhanced in an environment that is tempered by the immunosuppressive actions of ␣CD154, as has been indicated recently (6,23).…”

Section: Depletion Of Cd4 ϩ Cd25 ϩ T Cells In An Intact Mouse Resultsmentioning

confidence: 89%

CD154 on the surface of CD4+CD25+ regulatory t cells contributes to skin transplant tolerance

et al. 2003

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Analysis of the Cd40 and Cd28 Pathways on Alloimmune Responses by Cd4+ T Cells in Vivo1

Abstract: The CD40/CD40L pathway, but not the CD28/B7 pathway, is critical for CD4-mediated rejection responses, however, the responsible mechanisms remain unclear.

Cited by 17 publications

References 31 publications

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Cutting Edge: T Cell Requirement for CD28 Costimulation Is Due to Negative Regulation of TCR Signals by PTEN

CD154 on the surface of CD4+CD25+ regulatory t cells contributes to skin transplant tolerance

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