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: 19.75). 09/2010; 33(3):326-39. DOI: 10.1016/j.immuni.2010.09.006
Source: PubMed

ABSTRACT 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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    • "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 · 13.91 Impact Factor
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    • "Given that CD28 transduces co-stimulatory signals required for the activation and proliferation of naïve T cells, inhibition of CD28 signaling into responder T cells by CTLA-4 expressed on Tregs is a central mechanism of suppression for the following reasons. Since CTLA-4 shares the ligands CD80 and CD86 with CD28, but has higher affinity for both, CTLA-4 highly expressed on Tregs blocks co-stimulation via CD28 on conventional T cells (Tconv) by out-competing CD28 for CD80/CD86 ligands in the immunological synapse [36] [37]. Agonistic anti-CD28 monoclonal antibody can indeed abrogate in vitro Treg-mediated suppression, while mature DCs expressing CD80 and CD86 at high levels can also attenuate suppression [38–40]. "
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    ABSTRACT: Foxp3-expressing regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance and homeostasis. One of the key issues for understanding Treg immunobiology is to determine how they suppress excessive or aberrant immune responses. Although a number of molecules have been reported to contribute to Treg suppressive function, the importance and precise role of each molecule is not clear. In this review, we propose and discuss that two modes of suppression can be distinguished. In the physiological and steady state, activation of naïve T cells can be suppressed by natural Tregs via deprivation of activation signals including CD28 signal and IL-2 from antigen-reactive T cells, keeping the latter in a naïve state in lymphoid tissues. These deprivation mechanisms are transiently abrogated in inflammatory conditions, allowing T cells to respond to antigen. In contrast, in highly inflammatory environments, for example, in microbial infection, activated Tregs acquire the capacity to kill or inactivate effector T cells and antigen-presenting cells, for example, via granzyme/perforin formation and IL-10 secretion, thereby actively damping excessive immune responses. Understanding these processes will help effectively controlling physiological and pathological immune responses via Tregs.
    Seminars in Immunology 11/2011; 23(6):424-30. DOI:10.1016/j.smim.2011.10.002 · 6.12 Impact Factor
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