Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.

Invariant Natural Killer T cells (iNKT) are a versatile lymphocyte subset with important roles in both host defense and immunological tolerance. They express a highly conserved TCR which mediates recognition of the non-polymorphic, lipid-binding molecule CD1d. The structure of human iNKT TCRs is uni...

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Autores principales: Gediminas Matulis, Joseph P Sanderson, Nikolai M Lissin, Maria B Asparuhova, Gopal R Bommineni, Daniel Schümperli, Richard R Schmidt, Peter M Villiger, Bent K Jakobsen, Stephan D Gadola
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spelling oai:doaj.org-article:228093b8dfbf408ab4d907a528db008d2021-12-02T19:54:48ZInnate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.1544-91731545-788510.1371/journal.pbio.1000402https://doaj.org/article/228093b8dfbf408ab4d907a528db008d2010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20585371/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Invariant Natural Killer T cells (iNKT) are a versatile lymphocyte subset with important roles in both host defense and immunological tolerance. They express a highly conserved TCR which mediates recognition of the non-polymorphic, lipid-binding molecule CD1d. The structure of human iNKT TCRs is unique in that only one of the six complementarity determining region (CDR) loops, CDR3beta, is hypervariable. The role of this loop for iNKT biology has been controversial, and it is unresolved whether it contributes to iNKT TCR:CD1d binding or antigen selectivity. On the one hand, the CDR3beta loop is dispensable for iNKT TCR binding to CD1d molecules presenting the xenobiotic alpha-galactosylceramide ligand KRN7000, which elicits a strong functional response from mouse and human iNKT cells. However, a role for CDR3beta in the recognition of CD1d molecules presenting less potent ligands, such as self-lipids, is suggested by the clonal distribution of iNKT autoreactivity. We demonstrate that the human iNKT repertoire comprises subsets of greatly differing TCR affinity to CD1d, and that these differences relate to their autoreactive functions. These functionally different iNKT subsets segregate in their ability to bind CD1d-tetramers loaded with the partial agonist alpha-linked glycolipid antigen OCH and structurally different endogenous beta-glycosylceramides. Using surface plasmon resonance with recombinant iNKT TCRs and different ligand-CD1d complexes, we demonstrate that the CDR3beta sequence strongly impacts on the iNKT TCR affinity to CD1d, independent of the loaded CD1d ligand. Collectively our data reveal a crucial role for CDR3beta for the function of human iNKT cells by tuning the overall affinity of the iNKT TCR to CD1d. This mechanism is relatively independent of the bound CD1d ligand and thus forms the basis of an inherent, CDR3beta dependent functional hierarchy of human iNKT cells.Gediminas MatulisJoseph P SandersonNikolai M LissinMaria B AsparuhovaGopal R BommineniDaniel SchümperliRichard R SchmidtPeter M VilligerBent K JakobsenStephan D GadolaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 6, p e1000402 (2010)
institution DOAJ
collection DOAJ
language EN
topic Biology (General)
QH301-705.5
spellingShingle Biology (General)
QH301-705.5
Gediminas Matulis
Joseph P Sanderson
Nikolai M Lissin
Maria B Asparuhova
Gopal R Bommineni
Daniel Schümperli
Richard R Schmidt
Peter M Villiger
Bent K Jakobsen
Stephan D Gadola
Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
description Invariant Natural Killer T cells (iNKT) are a versatile lymphocyte subset with important roles in both host defense and immunological tolerance. They express a highly conserved TCR which mediates recognition of the non-polymorphic, lipid-binding molecule CD1d. The structure of human iNKT TCRs is unique in that only one of the six complementarity determining region (CDR) loops, CDR3beta, is hypervariable. The role of this loop for iNKT biology has been controversial, and it is unresolved whether it contributes to iNKT TCR:CD1d binding or antigen selectivity. On the one hand, the CDR3beta loop is dispensable for iNKT TCR binding to CD1d molecules presenting the xenobiotic alpha-galactosylceramide ligand KRN7000, which elicits a strong functional response from mouse and human iNKT cells. However, a role for CDR3beta in the recognition of CD1d molecules presenting less potent ligands, such as self-lipids, is suggested by the clonal distribution of iNKT autoreactivity. We demonstrate that the human iNKT repertoire comprises subsets of greatly differing TCR affinity to CD1d, and that these differences relate to their autoreactive functions. These functionally different iNKT subsets segregate in their ability to bind CD1d-tetramers loaded with the partial agonist alpha-linked glycolipid antigen OCH and structurally different endogenous beta-glycosylceramides. Using surface plasmon resonance with recombinant iNKT TCRs and different ligand-CD1d complexes, we demonstrate that the CDR3beta sequence strongly impacts on the iNKT TCR affinity to CD1d, independent of the loaded CD1d ligand. Collectively our data reveal a crucial role for CDR3beta for the function of human iNKT cells by tuning the overall affinity of the iNKT TCR to CD1d. This mechanism is relatively independent of the bound CD1d ligand and thus forms the basis of an inherent, CDR3beta dependent functional hierarchy of human iNKT cells.
format article
author Gediminas Matulis
Joseph P Sanderson
Nikolai M Lissin
Maria B Asparuhova
Gopal R Bommineni
Daniel Schümperli
Richard R Schmidt
Peter M Villiger
Bent K Jakobsen
Stephan D Gadola
author_facet Gediminas Matulis
Joseph P Sanderson
Nikolai M Lissin
Maria B Asparuhova
Gopal R Bommineni
Daniel Schümperli
Richard R Schmidt
Peter M Villiger
Bent K Jakobsen
Stephan D Gadola
author_sort Gediminas Matulis
title Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
title_short Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
title_full Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
title_fullStr Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
title_full_unstemmed Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop.
title_sort innate-like control of human inkt cell autoreactivity via the hypervariable cdr3beta loop.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/228093b8dfbf408ab4d907a528db008d
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