open access

https://hdl.handle.net/2115/63137

Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naïve T cells

A link between TCR-mediated signals and stress responses

英語

TCR signal

2016-03

Oxford University Press

International immunology

28(3)

117-126

KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo.

学術雑誌論文

Accepted Manuscript

This is a pre-copyedited, author-produced PDF of an article accepted for publication in International Immunology following peer review. The version of record, Int. Immunol. (2016) 28 (3): 117-126, is available online at: http://dx.doi.org/10.1093/intimm/dxv059

0953-8178

AA10730708