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.
"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 . "
[Show abstract][Hide abstract] 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.
"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 ."
[Show abstract][Hide abstract] 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.
"The lower-affinity H-2D b MHCI agonists behave more like the previously characterized CD4 T cell systems, where only a very restricted set of coagonist peptides can support enhancement. Previously proposed qualitative and mathematical models of coagonism studied in the context of CD4 T cells are closely related to the model we have studied here (Li et al., 2004; Krogsgaard et al., 2005 "
[Show abstract][Hide abstract] ABSTRACT: Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide-MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4-MHCII interaction is generally weaker than CD8-MHCI.
Journal of Experimental Medicine 08/2013; 210(9). DOI:10.1084/jem.20122528 · 12.52 Impact Factor
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