Abstract
MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nanoscale discoidal membrane mimetics (nanolipoprotein particles) to capture and present peptide–MHC (pMHC) ligands at various densities. We examined the binding of these model membrane clusters to the surface of live human CD8+ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8–MHC interactions, and relatively long lifetime of cognate TCR–pMHC complexes emerge as essential parameters, explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggests a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate Ag recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T cell responses.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 591-597 |
| Number of pages | 7 |
| Journal | Journal of Immunology |
| Volume | 202 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Extent of MHC clustering regulates selectivity and effectiveness of T cell responses. / Anikeeva, Nadia; Fischer, Nicholas O; Blanchette, Craig D.; Sykulev, Yuri.
In: Journal of Immunology, Vol. 202, No. 2, 15.01.2019, p. 591-597.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Extent of MHC clustering regulates selectivity and effectiveness of T cell responses
AU - Anikeeva, Nadia
AU - Fischer, Nicholas O
AU - Blanchette, Craig D.
AU - Sykulev, Yuri
PY - 2019/1/15
Y1 - 2019/1/15
N2 - MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nanoscale discoidal membrane mimetics (nanolipoprotein particles) to capture and present peptide–MHC (pMHC) ligands at various densities. We examined the binding of these model membrane clusters to the surface of live human CD8+ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8–MHC interactions, and relatively long lifetime of cognate TCR–pMHC complexes emerge as essential parameters, explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggests a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate Ag recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T cell responses.
AB - MHC proteins that present peptide ligands for recognition by TCR form nanoscale clusters on the cell membrane of APCs. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nanoscale discoidal membrane mimetics (nanolipoprotein particles) to capture and present peptide–MHC (pMHC) ligands at various densities. We examined the binding of these model membrane clusters to the surface of live human CD8+ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8–MHC interactions, and relatively long lifetime of cognate TCR–pMHC complexes emerge as essential parameters, explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggests a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate Ag recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T cell responses.
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U2 - 10.4049/jimmunol.1801196
DO - 10.4049/jimmunol.1801196
M3 - Article
C2 - 30541879
AN - SCOPUS:85059929185
VL - 202
SP - 591
EP - 597
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -