Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 7, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201763
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Funding
- Japan Agency for Medical Research and Development [JP20fk0108137]
- Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic [JP20wm0325010]
- Strategic International Collaborative Research Program [JP19jm0210067]
- Ministry of Education, Culture, Sports, Science and Technology [20H05771, 19H04809, 18KK0226, 18H02642, 19H00970]
- Joint Usage and Joint Research Programs of the Institute of Advanced Medical Sciences, Tokushima University
- Takeda Science Foundation
- Mochida Memorial Foundation
- Uehara Memorial Foundation
- Naito Foundation
- Astellas Foundation
- Research Foundation for Microbial Diseases of Osaka University
- Grants-in-Aid for Scientific Research [20H05771, 19H04809, 18H02642, 18KK0226] Funding Source: KAKEN
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The TCR signaling in CD8(+) T cells is qualitatively different from that in CD4(+) T cells due to the involvement of PLC beta 4. PLC beta 4 plays a crucial role in activating CD8(+) T cells and promoting adaptive immunity, while deficiency of PLC beta 4 leads to impaired immune responses in CD8(+) T cells.
Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4(+) and CD8(+) T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8(+) T cells is qualitatively different from that in CD4(+) T cells, since CD8 alpha ignites another cardinal signaling cascade involving phospholipase C beta 4 (PLC beta 4). TCR-mediated responses were severely impaired in PLC beta 4-deficient CD8(+) T cells, whereas those in CD4(+) T cells were intact. PLC beta 4-deficient CD8(+) T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLC beta 4 to the cytoplasmic tail of CD8 alpha was important for CD8(+) T cell activation. Furthermore, GNAQ interacted with PLC beta 4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLC beta 4, and activated CD8(+) T cells in a PLC beta 4-dependent fashion. PLC beta 4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLC beta 4 differentiates TCR signaling in CD4(+) and CD8(+) T cells and selectively promotes CD8(+) T cell-dependent adaptive immunity.
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