Functional avidity directs T-cell fate in autoreactive CD4(+) T cells

University of Washington Seattle, Seattle, Washington, United States
Blood (Impact Factor: 10.45). 11/2005; 106(8):2798-805. DOI: 10.1182/blood-2004-12-4848
Source: PubMed


Major histocompatibility complex class II tetramer staining and activation analysis identified 2 distinct types of antigen-specific CD4+ T cells in the peripheral blood of humans with type 1 (autoimmune) diabetes. T cells with low-avidity recognition of peptide-MHC ligands had low sensitivity to activation and inefficient activation-induced apoptosis. In contrast, high-avidity T cells were highly sensitive to antigen-induced cell death through apoptotic mechanisms, and both apoptosis-resistant high- and low-avidity T cells that survived prolonged tetramer treatment were rendered anergic to restimulation by antigen. In addition, however, apoptosis-resistant high-avidity T cells acquired regulatory features, being able to suppress both antigen-specific and nonspecific CD4+ T-cell responses. This suppression was contact-dependent and correlated with the down-regulation of HLA class II and costimulatory molecules on antigen-presenting cells, including B cells and dendritic cells. T cells face a variety of fates following antigen exposure, including the paradoxic maintenance of high-avidity autoreactive T cells in the peripheral circulation, perhaps due to this capability of acquiring anergic and suppressive properties. Regulation via down-modulation of antigen-presenting cell function, a form of cell-to-cell licensing for suppression, also offers possibilities for the application of peptide-MHC therapeutics.

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    • "The binding of TCRs to pMHCs occurs over a broad range avidity (Mallone et al., 2005; Reijonen et al., 2004) that is correlated with the pathogenic potential of T cells (Amrani et al., 2000). Experimental evidence suggests that, during T1D progression , T cells undergo a process of avidity maturation (Standifer et al., 2009), regulated by tolerance and competition (Amrani et al., 2000). "
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of insulin-secreting pancreatic β cells, leading to abolition of insulin secretion and onset of diabetes. Cytotoxic CD4(+) and CD8(+) T cells, activated by antigen presenting cells (APCs), are both implicated in disease onset and progression. Regulatory T cells (Tregs), on the other hand, play a leading role in regulating immunological tolerance and resistant homoeostasis in T1D by supressing effector T cells (Teffs). Recent data indicates that after activation, conventional Teffs transiently produce interleukin IL-2, a cytokine that acts as a growth factor for both Teffs and Tregs. Tregs suppress Teffs through IL-2 deprivation, competition and Teff conversion into inducible Tregs (iTregs). To investigate the interactions of these components during T1D progression, a mathematical model of T-cell dynamics is developed as a predictor of β-cell loss, with the underlying hypothesis that avidity of Teffs and Tregs, i.e., the binding affinity of T-cell receptors to peptide-major histocompatibility complexes on host cells, is continuum. The model is used to infer a set of criteria that determines susceptibility to T1D in high risk subjects. Our findings show that diabetes onset is guided by the absence of Treg-to-Teff dominance at specific high avidities, rather than over the whole range of avidity, and that the lack of overall dominance of Teffs-to-Tregs over time is the underlying cause of the "honeymoon period", the remission phase observed in some T1D patients. The model also suggests that competition between Teffs and Tregs is more effective than Teff-induction into iTregs in suppressing Teffs, and that a prolonged full width at half maximum of IL-2 release is a necessary condition for curbing disease onset. Finally, the model provides a rationale for observing rapid and slow progressors of T1D based on modest heterogeneity in the kinetic parameters.
    Journal of Theoretical Biology 08/2015; 383. DOI:10.1016/j.jtbi.2015.07.032 · 2.12 Impact Factor
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    • "This may be a particularly important limitation in the ability to detect anti-self and anti-tumor CD4+ T cell populations [7], [16]. In reality, only antigen-specific CD4+ T cells of the highest frequency, avidity and/or affinity may be detectable [17]. "
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    ABSTRACT: Targeting CD4+ T cells through their unique antigen-specific, MHC class II-restricted T cell receptor makes MHC class II tetramers an attractive strategy to identify, validate and manipulate these cells at the single cell level. Currently, generating class II tetramers is a specialized undertaking effectively limiting their use and emphasizing the need for improved methods of production. Using class II chains expressed individually in E. coli as versatile recombinant reagents, we have previously generated peptide-MHC class II monomers, but failed to generate functional class II tetramers. Adding a monomer purification principle based upon affinity-tagged peptides, we here provide a robust method to produce class II tetramers and demonstrate staining of antigen-specific CD4+ T cells. We also provide evidence that both MHC class II and T cell receptor molecules largely accept affinity-tagged peptides. As a general approach to class II tetramer generation, this method should support rational CD4+ T cell epitope discovery as well as enable specific monitoring and manipulation of CD4+ T cell responses.
    PLoS ONE 12/2013; 8(9):e73648. DOI:10.1371/journal.pone.0073648 · 3.23 Impact Factor
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    • "Numerous studies have described the possible outcomes, such as full priming, partial activation, unresponsiveness, or induction of apoptosis, following administration of pMHCI to CTL in vitro and in vivo [10, 44–46]. Similar results have been detected in human T H treated with pMHCII multimers [47] [48]. Such varying effects of pMHC administration upon modulation of diabetogenic T cells will be highlighted later, but are likely due to pMHC multimer avidity, functional plasticity of the clonotype targeted, and the molecule conjugated to the pMHC multimer. "
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    ABSTRACT: Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.
    Clinical and Developmental Immunology 05/2012; 2012:380289. DOI:10.1155/2012/380289 · 2.93 Impact Factor
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