Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells.
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.
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Daisuke
D
Kamimura
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Yasunobu
Y
Arima
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Mineko
M
Tsuruoka
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Jing-Jing
JJ
Jiang
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Hidenori
H
Bando
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Jie
J
Meng
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Lavannya
L
Sabharwal
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan.
Andrea
A
Stofkova
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan.
Naoki
N
Nishikawa
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan.
Kotaro
K
Higuchi
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Hideki
H
Ogura
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Toru
T
Atsumi
Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, Hokkaido 060-0815, Japan Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan murakami@igm.hokudai.ac.jp.
Masaaki
M
Murakami
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D018956:CD5 Antigens / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology*
D001324:Autoantigens; D018956:CD5 Antigens; C000606768:KDELR1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018000:Receptors, Peptide
KDEL receptors; T-cell homeostasis; TCR signal; stress responses