The Serial Engagement Model 17 Years After: From TCR Triggering to Immunotherapy

Valitutti, Salvatore

doi:10.3389/fimmu.2012.00272

Cited by 46 publications

(35 citation statements)

References 64 publications

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“…5) show precisely the opposite pattern; i.e., the CD4-35-17b CAR (with a linker sufficiently long to enable bispecific binding) was consistently less potent than the CD4-10-17b CAR (with a linker too short for bispecific binding). These findings are consistent with the requirement for serial TCR/peptide-MHC engagement for optimal functionality, as originally proposed (68) and subsequently expanded to include influences of cytoskeletal interactions that modulate cellular dynamics at the immunological synapse (69,70). Current models emphasize the importance of rapid dissociation and reformation of TCR-peptide/MHC bonds; moreover, they highlight the reduced sensitivity to low antigen densities associated with unnaturally high binding affinities.…”

Section: Discussionsupporting

confidence: 72%

Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

Liu

Patel

Ghanem

et al. 2015

J Virol

103

133

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Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-␥) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8 ؉ T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit. IMPORTANCEHIV research has been energized by prospects for a cure for HIV infection or, at least, for a "functional cure" whereby antiretroviral therapy can be discontinued without virus rebound. This report describes a novel CD4-based "chimeric antigen receptor" (CAR) which, when genetically engineered into T cells, gives them the capability to selectively respond to and kill HIV-infected cells. This CAR displays enhanced features compared to previously described CD4-based CARs, namely, increased potency and avoidance of the undesired rendering of the genetically modified CD8 T cells susceptible to HIV infection. When adoptively transferred back to the individual, the genetically modified T cells will hopefully provide durable killing of infected cells and sustained virus suppression without continued antiretroviral therapy, i.e., a functional cure. C ombination antiretroviral therapy (cART) (1) today offers the promise of near-normal life expectancy for HIV-infected individuals (2), most of whom would previously have succumbed to the lethal consequences of immune system demise. Nevertheless, even under conditions of plasma viral load suppression below the limits of detection, CD4 T-cell recovery is often incomplete. The pathogenic sequel...

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Section: Discussionsupporting

confidence: 72%

Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

Liu

Patel

Ghanem

et al. 2015

J Virol

103

133

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“…The kinetic proofreading model (61), for example, proposed that the TCR needs to undergo a series of intermediate steps before being triggered so that the overall response depends on the TCR-pMHC dissociation time. Other models propose an optimal dwell time for TCR-pMHC interactions (62) or serial engagement of different TCRs by the same pMHC (57,63). In all of these models, the intermediate steps are necessary for antigen discrimination.…”

Section: Discussionmentioning

confidence: 99%

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Pageon

Tabarin

Yamamoto

et al. 2016

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

199

235

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Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination.

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“…The model rests on evidence that many TCRs on a single T cell are downregulated in the presence of small numbers of pMHC molecules. Serial engagement has morphed over years to incorporate arguments germane to 2D vs. 3D apparent binding kinetics (77), rationalizing the requirements for optimal TCR affinity to avoid interactions that are too strong or too weak to achieve repeat binding and sustained T-cell signaling (18). Liu et al (19) suggested that serial engagement is occurring through early and rapidly accumulated bond lifetimes.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, T cells confronting "weakly" interacting ligands are able to sense and discriminate antigens with exquisite specificity, even detecting single-amino acid differences between two peptides bound to the same MHC allele product (16). A serial engagement process where a single (or low copy number) antigenic pMHC binds and unbinds multiple receptors (hundreds) on a T cell to amplify and sustain its activation has been proposed to generate signaling through fleeting encounters, including those important for antitumor immunity (17,18). The original concept of serial engagement (or serial triggering) was based on reutilization of pMHC over a period of hours that has been recently redefined to encompass shorter cycles of TCR stimulation over a period of seconds (19).…”

mentioning

confidence: 99%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

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

155

197

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T lymphocytes use surface αβ T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction (∼10 pN per TCR molecule) triggers T-cell Ca 2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via ∼8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers.mechanosensor | T-cell receptor | T-cell activation | optical tweezers | cellular force relaxation T he T-cell receptor (TCR) expressed on T lymphocytes of the adaptive immune system is a stout and squat (12-nm wide × 8-nm tall) multisubunit surface complex with a ligand binding moiety that is an αβ disulfide-linked heterodimer buttressed by the associated invariant CD3 subunits (1-3). The αβ chains are each encoded by V and J gene segments and in the case of the β, a D segment as well (4). The clone-specific TCR unique to each T lymphocyte endows mammals with the capacity to detect perturbations in host cellular function resulting from myriad infectious pathogens, physical damage (thermal, irradiation, etc.), or premalignant or malignant cellular transformations while averting strong self-reactivities that could induce autoimmunity (5).Signaling is initiated through ligation of the clonotype by its cognate antigenic peptide bound to an MHC molecule (pMHC) and displayed on the surface of antigen-presenting cells (APCs) (6, 7). Ligation impacts disposition and function of the associated CD3 dimers (CD3 γ, CD3 δ, and CD3ζζ) as well as the transmembrane domains of the TCR heterodimer and CD3 subunits that interdigitate in the membrane to signal into the cytoplasm (8, 9). A cascade of intracellular events involving phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 cytoplasmic domains with subsequent ZAP70 activation and downstream signaling follows (10, 11). Membrane-associated CD8 and CD4 coreceptors, marking cytotoxic T lymphocytes (CTLs) and helper T cells, respectively, function to bring the membrane-anchored Src family tyrosine kinase Lck to the TCR-pMHC complex for the initiation of ITAM phosphorylation. Signaling, in turn, leads to a transient rise of cytosolic Ca 2+ and other biochemical events resulting in transcriptional activation, ultimately resulting in developmental decisions or effector functi...

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The Serial Engagement Model 17 Years After: From TCR Triggering to Immunotherapy

Cited by 46 publications

References 64 publications

Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Mechanosensing drives acuity of αβ T-cell recognition

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