Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity

Romain Bedel, Richard Berry, Thierry Mallevaey, Jennifer L Matsuda, JingJing Zhang, Dale I Godfrey, Jamie Rossjohn, John Kappler, Philippa Marrack, Laurent Gapin

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26 Citations (Scopus)

Abstract

The self-reactivity of their T-cell antigen receptor (TCR) is thought to contribute to the development of immune regulatory cells, such as invariant NK T cells (iNKT). In the mouse, iNKT cells express TCRs composed of a unique Valpha14-Jalpha18 rearrangement and recognize lipid antigens presented by CD1d molecules. We created mice expressing a transgenic TCR-beta chain that confers high affinity for self-lipid/CD1d complexes when randomly paired with the mouse iNKT Valpha14-Jalpha18 rearrangement to study their development. We show that although iNKT cells undergo agonist selection, their development is also shaped by negative selection in vivo. In addition, iNKT cells that avoid negative selection in these mice express natural sequence variants of the canonical TCR-alpha and decreased affinity for self/CD1d. However, limiting the affinity of the iNKT TCRs for self leads to inefficient Egr2 induction, poor expression of the iNKT lineage-specific zinc-finger transcription factor PLZF, inadequate proliferation of iNKT cell precursors, defects in trafficking, and impaired effector functions. Thus, proper development of fully functional iNKT cells is constrained by a limited range of TCR affinity that plays a key role in triggering the iNKT cell-differentiation pathway. These results provide a direct link between the affinity of the TCR expressed by T-cell precursors for self-antigens and the proper development of a unique population of lymphocytes essential to immune responses.
Original languageEnglish
Pages (from-to)E119 - E128
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
Publication statusPublished - 2014

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