A Synaptic Basis for Paracrine Interleukin-2 Signaling during Homotypic T Cell Interaction

Sabatos, Catherine A.; Doh, Junsang; Chakravarti, Sumone; Friedman, Rachel S.; Pandurangi, Priya; Tooley, Aaron J.; Krummel, Matthew F.

doi:10.1016/j.immuni.2008.05.017

Cited by 128 publications

(159 citation statements)

References 36 publications

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“…It is becoming better appreciated that, during the course of their activation, T cells form substantial homo-and heterotypic clusters around the activating APC and that direct T cell-T cell signaling occurs within these clusters (52)(53)(54)(55)(56). In the context of our study, we believe that critical CD28-B7 interactions may be occurring within these T cell clusters.…”

Section: Discussionmentioning

confidence: 63%

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Rudulier

McKinstry

Al‐Yassin

et al. 2014

The Journal of Immunology

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Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.

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Section: Discussionmentioning

confidence: 63%

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Rudulier

McKinstry

Al‐Yassin

et al. 2014

The Journal of Immunology

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“…Effects of T-cell-T-cell interactions involving CD80 and CTLA-4 have been observed in vivo (38) and suggested previously to induce anergy (39). Furthermore, these activated T-cell-T-cell interactions have been directly visualized in vivo and shown to occur through stable, multifocal synapse-like structures (40) to which the microtubule-organizing complex polarizes. Of interest in this regard is the observation that CTLA-4 localizes to the microtubule-organizing complex (41).…”

Section: Discussionmentioning

confidence: 84%

Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8⁺T cell

Thaventhiran

Hoffmann

Magiera

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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During the primary response, the commitment of the CD8 + T cell to Blimp-1 expression and the terminal differentiation that Blimp-1 induces must be timed so as not to impair the process of clonal expansion. We determined whether the Hippo pathway, which links cell–cell contact to differentiation in other cell lineages, controls Blimp-1 expression. Activating the CD8 + T cell with antigen and IL-2 causes expression of the core Hippo pathway components, including the pivotal transcriptional cofactor Yap. Contact between activated CD8 + T cells induces Hippo pathway-mediated Yap degradation and Blimp-1 expression; a Hippo-resistant, stable form of Yap suppresses Blimp-1 expression. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and CD80 comprise the receptor–ligand pair that mediates contact-dependent Hippo pathway activation. In vivo, CD8 + T cells expressing Hippo resistant-Yap or lacking CTLA-4 have diminished expression of the senescence marker, KLRG1, during a viral infection. The CTLA-4/Hippo pathway/Blimp-1 system may couple terminal differentiation of CD8 + T cell with the magnitude of clonal expansion.

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“…Homotypic interactions within such clusters enable direct polarized cytokine delivery to promote activation responses and are dependent on LFA-1 activity (27). Within the OP9-DL1 coculture system, LFA-1 is clustered at sites of contact between immature T cells.…”

Section: Discussionmentioning

confidence: 99%

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Pike

Kulkarni

Pawson

2010

Proc. Natl. Acad. Sci. U.S.A.

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T-cell polarization is required for cell migration and cell-cell interactions, cellular behaviors crucial for lymphocyte differentiation. Despite expression of the epithelial polarity network in T cells, neither its contribution to thymocyte polarity nor its requirement during development is known. We report here that depletion of the polarity protein Scribble in hematopoietic progenitor cells results in inefficient T-cell development characterized by a partial developmental block during the early double-negative (DN) stage of differentiation. Scribble-depleted hematopoietic progenitor cells exhibit a delayed transition into late CD44 lo/− CD25 + DN3 cells, evidenced by the accumulation of early CD44 int CD25 + DN3 cells. As a consequence, a limited cellular expansion and a reduced frequency of intracellular T-cell receptor β-positive DN3 cells are observed among Scribble-deficient differentiating T cells. Moreover, whereas purified Scribble-depleted DN2 and DN3 cells do not exhibit compromised spontaneous motility, T-cell clustering and prolonged homotypic interactions among such cells are reduced. This deficiency correlates with a lack of polarization of the integrin LFA-1 during T-cell migration or on the initiation of T-cell-T-cell interactions. Scribble is therefore a critical contributor to the clustering of immature T cells, an event shown here to be necessary for efficient developmental progression.

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A Synaptic Basis for Paracrine Interleukin-2 Signaling during Homotypic T Cell Interaction

Cited by 128 publications

References 36 publications

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8⁺T cell

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

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A Synaptic Basis for Paracrine Interleukin-2 Signaling during Homotypic T Cell Interaction

Cited by 128 publications

References 36 publications

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+T cell

Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

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Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8⁺T cell