Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion

Yu Hu, Ji Hyung Kim, Kangmin He, Qi Wan, Jessica Kim, Melanie Flach, Tom Kirchhausen, Andrea Vortkamp, Florian Winau

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2759-2772
Number of pages14
JournalJournal of Experimental Medicine
Volume213
Issue number12
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

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T-Cell Antigen Receptor
T-Lymphocytes
Multivesicular Bodies
Endosomes
Virus Diseases
Infection
Viral Load
Communicable Diseases
Phospholipids
Chronic Disease
Cytokines
Lipids
Membranes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. / Hu, Yu; Kim, Ji Hyung; He, Kangmin; Wan, Qi; Kim, Jessica; Flach, Melanie; Kirchhausen, Tom; Vortkamp, Andrea; Winau, Florian.

In: Journal of Experimental Medicine, Vol. 213, No. 12, 01.01.2016, p. 2759-2772.

Research output: Contribution to journalArticle

Hu, Y, Kim, JH, He, K, Wan, Q, Kim, J, Flach, M, Kirchhausen, T, Vortkamp, A & Winau, F 2016, 'Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion', Journal of Experimental Medicine, vol. 213, no. 12, pp. 2759-2772. https://doi.org/10.1084/jem.20160612
Hu, Yu ; Kim, Ji Hyung ; He, Kangmin ; Wan, Qi ; Kim, Jessica ; Flach, Melanie ; Kirchhausen, Tom ; Vortkamp, Andrea ; Winau, Florian. / Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 12. pp. 2759-2772.
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