Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Anikeeva, Nadia; Fischer, Nicholas O.; Blanchette, Craig D.; Sykulev, Yuri

doi:10.4049/jimmunol.1801196

Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Journal Article · Mon Jan 07 00:00:00 EST 2019 · Journal of Immunology

DOI:https://doi.org/10.4049/jimmunol.1801196· OSTI ID:1497300

Anikeeva, Nadia ^[1]; Fischer, Nicholas O. ^[2]; Blanchette, Craig D. ^[2]; ^[1]

Thomas Jefferson Univ., Philladelphia, PA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

MHC proteins that present peptide ligands for recognition by T-cell antigen receptor (TCR) form nano-scale clusters on the cell membrane of antigen-presenting cells. 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 nano-scale discoidal membrane mimetics (nanolipoprotein particles, or NLPs) to capture and present pMHC ligands at various densities. We examined the binding of these model membrane clusters to the surface of live 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 TCRpMHC complexes emerge as essential parameters explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggested 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 antigen recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T-cell responses.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1497300

Report Number(s):: LLNL-JRNL--737703; 890710

Journal Information:: Journal of Immunology, Journal Name: Journal of Immunology Journal Issue: 2 Vol. 202; ISSN 0022-1767

Publisher:: The American Association of Immunologists, Inc.Copyright Statement

Country of Publication:: United States

Language:: English

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