Article

Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238-243

The Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 41.46). 04/2005; 434(7030):238-43. DOI: 10.1038/nature03391
Source: PubMed

ABSTRACT

Alphabeta T lymphocytes are able to detect even a single peptide-major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This is despite clear evidence, at least with CD4+ T cells, that monomeric ligands are not stimulatory. In an effort to understand how this remarkable sensitivity is achieved, we constructed soluble peptide-MHC heterodimers in which one peptide is an agonist and the other is one of the large number of endogenous peptide-MHCs displayed by presenting cells. We found that some specific combinations of these heterodimers can stimulate specific T cells in a CD4-dependent manner. This activation is severely impaired if the CD4-binding site on the agonist ligand is ablated, but the same mutation on an endogenous ligand has no effect. These data correlate well with analyses of lipid bilayers and cells presenting these ligands, and indicate that the basic unit of helper T cell activation is a heterodimer of agonist peptide- and endogenous peptide-MHC complexes, stabilized by CD4.

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    • "The extracellular domain of CD8 binds to the í µí»¼ 3 -domain of the MHC class I heavy chain [2]. It is well-known that CD8 and CD4 coreceptors are able to enhance T-cell responses to antigen stimulation [3] [4] [5]. Also, when subjected to an immune response, CD8 + T-cells can substantially increase in sensitivity by the mechanism of functional avidity maturation , that is, maturation of strength of multivalent antigenantibody binding [6] [7] [8]. "
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    ABSTRACT: Molecular dynamics was used to simulate large molecules of the immune system (major histocompatibility complex class I, presented epitope, T-cell receptor, and a CD8 coreceptor.) To characterize the relative orientation and movements of domains local coordinate systems (based on principal component analysis) were generated and directional cosines and Euler angles were computed. As a most interesting result, we found that the presence of the coreceptor seems to influence the dynamics within the protein complex, in particular the relative movements of the two α -helices, G α 1 and G α 2 .
    Full-text · Article · Dec 2015 · Journal of Immunology Research
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    • "In the pseudodimer model, TCR forms a dimer based on binding one agonist pMHC class II, which also binds CD4, and one self-pMHC, which binds much more transiently. The TCR bound to the self pMHC is then efficiently phosphorylated by Lck (lymphocyte-specific protein tyrosine kinase) associated with the CD4 (Krogsgaard et al., 2005). This model was well supported by the ability of soluble heterodimers of agonist pMHC and self-pMHC to trigger T cell activation when applied in solution . "
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    ABSTRACT: Molecular interactions at the interface between helper T cells and antigen-presenting B cells govern the ability to produce specific antibodies, which is a central event in protective immunity generated by natural infection or man-made vaccines. In order for a T cell to deliver effective help to a B cell and guide affinity maturation, it needs to provide feedback that is proportional to the amount of antigen the B cell collects with its surface antibody. This review focuses on mechanisms by which T and B cells manage to count the products of antigen capture and encourage B cells with the best receptors to dominate the response and make antibody-producing plasma cells. We discuss what is known about the proportionality of T cells responses to presented antigens and consider the mechanisms that B cells may use to keep count of positive feedback from T cells.
    Full-text · Article · Apr 2014 · Molecular cell
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    • "e recruitment and activation of downstream signaling mole - cules , consistent with the kinetic segregation model ( Choudhuri et al . , 2005 ; Davis and van der Merwe , 2006 ; James and Vale , 2012 ; van der Merwe and Dushek , 2011 ) . Along with the involve - ment of weakly stimulatory endogenous coagonist pMHCs abundantly presented by the APCs ( Krogsgaard et al . , 2005 ) , this process could result in the sustained and amplified signaling required for the low threshold and digital cytokine responses in T cells ."
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    ABSTRACT: We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4(+) T cell functional sensitivity. We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼1,000, ∼10,000, and ∼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4(+) T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell.
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