Spatiotemporal Basis of CTLA-4 Costimulatory Molecule-Mediated Negative Regulation of T Cell Activation

Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Immunity (Impact Factor: 21.56). 09/2010; 33(3):326-39. DOI: 10.1016/j.immuni.2010.09.006
Source: PubMed


T cell activation is positively and negatively regulated by a pair of costimulatory receptors, CD28 and CTLA-4, respectively. Because these receptors share common ligands, CD80 and CD86, the expression and behavior of CTLA-4 is critical for T cell costimulation regulation. However, in vivo blocking of CD28-mediated costimulation by CTLA-4 and its mechanisms still remain elusive. Here, we demonstrate the dynamic behavior of CTLA-4 in its real-time competition with CD28 at the central-supramolecular activation cluster (cSMAC), resulting in the dislocalization of protein kinase C-θ and CARMA1 scaffolding protein. CTLA-4 translocation to the T cell receptor microclusters and the cSMAC is tightly regulated by its ectodomain size, and its accumulation at the cSMAC is required for its inhibitory function. The CTLA-4-mediated suppression was demonstrated by the in vitro anergy induction in regulatory T cells constitutively expressing CTLA-4. These results show the dynamic mechanism of CTLA-4-mediated T cell suppression at the cSMAC.

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Available from: Hu Zeng, Apr 17, 2014
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    • "It would be interesting to determine whether a CD28-Lck-PKCθ tri-partite complex (Kong et al., 2011) occurs in T reg cells, and determine the mechanism that enables PKCθ recruitment away from the T reg -APC contact area. A possible explanation for this process was provided by Yokosuka et al. (2010) showing that CTLA-4 competes with CD28 in recruitment to the cSMAC. In addition, it is not known whether PKCθ is involved in a second signal delivery during the costimulation of γδ T cells (Ribot et al., 2011). "
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    ABSTRACT: 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 TCR and the CD28 costimulatory receptor. TCR/CD28 engagement triggers the translocation of the cytosolic PKCθ to the plasma membrane, 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). The cellular redistribution of PKCθ in resting versus activated T cells has been thoroughly investigated, but the mechanisms governing its translocation to the center of the IS, and how this unique localization relates to the biological activity of PKCθ have remained unclear until recently. A very recent study has shown that the unique V3 (hinge) domain of PKCθ 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 the Lck as an intermediate. Furthermore, the PKCθ-CD28 complex, which forms upon antigen stimulation, is localized at a newly recognized, TCRlow subregion of the central IS, where it forms an outer ring around the very center, TCRhigh subregion. Importantly, the association of PKCθ with CD28 is also essential for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT, which are sine qua non for the productive activation of T lymphocytes. Indeed, the use of V3-altered PKCθ mutants or the isolated V3 domain as a negative dominant mutant demonstrated that strategies, which disrupt the interaction between PKCθ and CD28, block T cell activation, proliferation and differentiation into pathogenic Th2 and Th17 (but not Th1) effector helper T cells. The recent progress made in understanding of the mechanism of recruitment and regulation of PKCθ activity at the IS is likely to facilitate the development of PKCθ-based therapeutic modalities for T cell-mediated diseases.
    Frontiers in Immunology 08/2012; 3:273. DOI:10.3389/fimmu.2012.00273
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    • "CTLA-4 is also essential for Treg suppression, as Treg-specific CTLA-4 knockout mice succumb to a severe autoimmune syndrome (Wing et al., 2008). CTLA-4 blocks T cell activation by physically removing CD80 and CD86 from dendritic cells, thus depriving effector T cells of costimulation (Yokosuka et al., 2010; Qureshi et al., 2011). CTLA-4 binding can also instruct dendritic cells to release indoleamine 2,3-dioxygenase, which produces pro-apoptotic kyneurenines and deprives proliferating T cells of the tryptophan needed for growth (Grohmann et al., 2002). "
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    ABSTRACT: Regulatory T cells (Tregs) prevent autoimmunity and inflammation by suppressing the activation of other T cells and antigen presenting cells. The role of phosphoinositide 3-kinase (PI3K) signaling in Treg is controversial. Some studies suggest that inhibition of the PI3K pathway is essential for the development of Tregs whereas other studies have shown reduced Treg numbers and function when PI3K activity is suppressed. Here we attempt to reconcile the different studies that have explored PI3K and the downstream effectors Akt, Foxo, and mTOR in regulatory T cell development and function and discuss the implications for health and therapeutic intervention.
    Frontiers in Immunology 08/2012; 3:244. DOI:10.3389/fimmu.2012.00244
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    • "PD-1 was accumulated into the same clusters with TCRs (PD-1–TCR microclusters) in the cells settled onto a planar bilayer containing PD-L1–GPI (Fig. 1 C, left) and 98% of TCR microclusters were colocalized with PD-1 (Fig. 1 D). In parallel with the c-SMAC formation by TCRs, PD-1 segregated from TCRs and accumulated predominantly at the TCR/CD3 lo region within the c-SMAC (as the signaling c-SMAC; Yokosuka et al., 2008; Yokosuka and Saito, 2010; Fig. 1 "
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    ABSTRACT: Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1-mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1-TCR colocalization within microclusters is required for efficient PD-1-mediated suppression. This inhibitory mechanism also functions in PD-1(hi) T cells generated in vivo and can be overridden by a neutralizing anti-PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.
    Journal of Experimental Medicine 05/2012; 209(6):1201-17. DOI:10.1084/jem.20112741 · 12.52 Impact Factor
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