Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion.
In chronic infection, T cells become hyporesponsive to antigenic stimulation to prevent immunopathology. Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes. TMEM16F is located in late endosomes, where it facilitates the generation of multivesicular bodies for TCR degradation and signal termination. Consequently, TMEM16F deficiency results in sustained signaling and augmented T cell activation. Our results demonstrate that scramblase restricts TCR responses to avoid overactivation, ensuring a well-balanced immune response in chronic infectious disease.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Yu
0000-0002-9511-9383
Y
Hu
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Ji Hyung
JH
Kim
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Kangmin
K
He
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Qi
Q
Wan
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Jessica
J
Kim
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Melanie
0000-0002-0590-8320
M
Flach
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Tom
0000-0003-0559-893X
T
Kirchhausen
Department of Developmental Biology, University Duisburg-Essen, 45117 Essen, Germany.
Andrea
A
Vortkamp
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 florian.winau@childrens.harvard.edu.
Florian
F
Winau
D000199:Actins / Q000378:metabolism; D000818:Animals; D000075368:Anoctamins; D002908:Chronic Disease; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D057146:Multivesicular Bodies / Q000378:metabolism / Q000648:ultrastructure; D009218:Myosins / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism
C576687:ANO6 protein, mouse; D000199:Actins; D000075368:Anoctamins; D049294:Phospholipid Transfer Proteins; D011948:Receptors, Antigen, T-Cell; D009218:Myosins; D020691:rab GTP-Binding Proteins