How the T cell signaling network processes information to discriminate between self and agonist ligands
| Autor: | Raman Ganti, Arup K. Chakraborty, Arthur Weiss, Darren McAffee, Wan-Lin Lo, Jay T. Groves |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class T-Lymphocytes T cell Receptors Antigen T-Cell Antigen-Presenting Cells Ligands Lymphocyte Activation Major histocompatibility complex Major Histocompatibility Complex Jurkat Cells 03 medical and health sciences 0302 clinical medicine Negative feedback medicine Humans Phosphorylation Adaptor Proteins Signal Transducing 030304 developmental biology Positive feedback 0303 health sciences Multidisciplinary biology Chemistry T-cell receptor Membrane Proteins Models Theoretical Peptide Fragments Cell biology Kinetics medicine.anatomical_structure Physical Sciences biology.protein Kinetic proofreading 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback. |
| Databáze: | OpenAIRE |
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