Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity.
T cell receptor (TCR) plays a fundamental role in adaptive immunity, and TCR-T cell therapy holds great promise for treating solid tumors and other diseases. However, there is a noticeable absence of chemical tools tuning TCR activity. In our study, we screened natural sterols for their regulatory effects on T cell function and identified 7-alpha-hydroxycholesterol (7a-HC) as a potent inhibitor of TCR signaling. Mechanistically, 7a-HC promoted membrane binding of CD3ε cytoplasmic domain, a crucial signaling component of the TCR-CD3 complex, through alterations in membrane physicochemical properties. Enhanced CD3ε membrane binding impeded the condensation between CD3ε and the key kinase Lck, thereby inhibiting Lck-mediated TCR phosphorylation. Transient treatments of TCR-T cells with 7a-HC resulted in reduced signaling strength, increased memory cell populations, and superior long-term antitumor functions. This study unveils a chemical regulation of TCR signaling, which can be exploited to enhance the long-term efficacy of TCR-T cell therapy.
Pubmed ID: 38759618 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Annexin V Apoptosis Detection Kit APC 200 tests Kit (RRID:AB_2575166)
- CD3-zeta (C-20) (RRID:AB_631130)
- Anti-Phosphotyrosine, 4G10 Platinum, HRP Conjugate (RRID:AB_1587393)
- GST (Z-5) (RRID:AB_631586)
- PLC gamma1 (1249) (RRID:AB_632202)
- CD3-zeta (6B10.2) (RRID:AB_627020)
- CD8a Monoclonal Antibody (53-6.7), APC, eBioscience (RRID:AB_469335)
- CD69 Monoclonal Antibody (H1.2F3), PE, eBioscience (RRID:AB_465732)
- CD62L (L-Selectin) Monoclonal Antibody (MEL-14), APC, eBioscience (RRID:AB_469410)
- CD8a Monoclonal Antibody (53-6.7), eFluor™ 450, eBioscience (RRID:AB_1272198)
- HRP GAPDH (RRID:AB_2631280)
- CD45.1 Monoclonal Antibody (A20), PE, eBioscience (RRID:AB_465675)
- CD8a Monoclonal Antibody (SK1), FITC, eBioscience (RRID:AB_10557240)
- CD69 Monoclonal Antibody (FN50), PE, eBioscience (RRID:AB_10733526)
- CD45RA Monoclonal Antibody (HI100), PE-Cyanine7, eBioscience (RRID:AB_1548774)
- Goat anti-Mouse IgG (H+L) Secondary Antibody (RRID:AB_228297)
- CD3 Monoclonal Antibody (OKT3), Functional Grade, eBioscience (RRID:AB_468855)
- CD8a Monoclonal Antibody (53-6.7), FITC, eBioscience (RRID:AB_464915)
- CD28 Monoclonal Antibody (CD28.2), Functional Grade, eBioscience (RRID:AB_468927)
- CD62L (L-Selectin) Monoclonal Antibody (DREG-56 (DREG56)), APC, eBioscience (RRID:AB_10671132)
- TCR beta Monoclonal Antibody (H57-597), PE, eBioscience (RRID:AB_466066)
- Biotin anti-mouse CD28 (RRID:AB_312869)
- Anti-Zap-70, phospho (Tyr319) / Syk, phospho (Tyr352) Antibody, Unconjugated (RRID:AB_331600)
- Phospho-PLCgamma1 (Tyr783) Antibody (RRID:AB_330855)
- Anti-mouse IgG, HRP-linked Antibody (RRID:AB_330924)
- Anti-rabbit IgG, HRP-linked Antibody (RRID:AB_2099233)
- PE anti-human CD197 (CCR7) (RRID:AB_10916391)
- Brilliant Violet 421(TM) anti-human CD279 (PD-1) (RRID:AB_10960742)
- PE/Cyanine7 anti-human CD223 (LAG-3) (RRID:AB_2629753)
- Brilliant Violet 785(TM) anti-mouse CD25 (RRID:AB_2564131)
- Ultra-LEAF(TM) Purified anti-mouse CD28 (RRID:AB_11147170)
- PE/Cyanine7 anti-human/mouse/rat CD278 (ICOS) (RRID:AB_10643411)
- Biotin anti-mouse CD3epsilon (RRID:AB_312669)
- Ultra-LEAF(TM) Purified anti-mouse CD3epsilon (RRID:AB_11149115)
- Brilliant Violet 421(TM) anti-mouse TCR beta chain (RRID:AB_2562562)
- PE Mouse Anti-TCF-7/TCF-1 Antibody (RRID:AB_2687845)
- Pacific Blue(TM) anti-human CD4 (RRID:AB_1595438)
- ZAP70 antibody [E267] (RRID:AB_778968)
- CD3 zeta (phospho Y142) antibody [EP265(2)Y] (RRID:AB_11156649)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
Annexin V Apoptosis Detection Kit APC 200 tests Kit (antibody)
RRID:AB_2575166
This unknown targets Annexin V
View all literature mentionsCD3-zeta (C-20) (antibody)
RRID:AB_631130
This polyclonal targets CD247
View all literature mentionsAnti-Phosphotyrosine, 4G10 Platinum, HRP Conjugate (antibody)
RRID:AB_1587393
This monoclonal targets Phosphotyrosine 4G10 Platinum HRP Conjugate
View all literature mentionsPLC gamma1 (1249) (antibody)
RRID:AB_632202
This polyclonal targets PLC gamma1 (1249)
View all literature mentionsCD3-zeta (6B10.2) (antibody)
RRID:AB_627020
This monoclonal targets CD247
View all literature mentionsCD8a Monoclonal Antibody (53-6.7), APC, eBioscience (antibody)
RRID:AB_469335
This monoclonal targets CD8a
View all literature mentionsCD69 Monoclonal Antibody (H1.2F3), PE, eBioscience (antibody)
RRID:AB_465732
This monoclonal targets CD69
View all literature mentionsCD62L (L-Selectin) Monoclonal Antibody (MEL-14), APC, eBioscience (antibody)
RRID:AB_469410
This monoclonal targets CD62L (L-Selectin)
View all literature mentionsCD8a Monoclonal Antibody (53-6.7), eFluor™ 450, eBioscience (antibody)
RRID:AB_1272198
This monoclonal targets CD8a
View all literature mentionsCD45.1 Monoclonal Antibody (A20), PE, eBioscience (antibody)
RRID:AB_465675
This monoclonal targets CD45.1
View all literature mentionsCD8a Monoclonal Antibody (SK1), FITC, eBioscience (antibody)
RRID:AB_10557240
This monoclonal targets CD8a
View all literature mentionsCD69 Monoclonal Antibody (FN50), PE, eBioscience (antibody)
RRID:AB_10733526
This monoclonal targets CD69
View all literature mentionsCD45RA Monoclonal Antibody (HI100), PE-Cyanine7, eBioscience (antibody)
RRID:AB_1548774
This monoclonal targets CD45RA
View all literature mentionsGoat anti-Mouse IgG (H+L) Secondary Antibody (antibody)
RRID:AB_228297
This polyclonal secondary targets IgG (H+L)
View all literature mentionsCD3 Monoclonal Antibody (OKT3), Functional Grade, eBioscience (antibody)
RRID:AB_468855
This monoclonal targets CD3
View all literature mentionsCD8a Monoclonal Antibody (53-6.7), FITC, eBioscience (antibody)
RRID:AB_464915
This monoclonal targets CD8a
View all literature mentionsCD28 Monoclonal Antibody (CD28.2), Functional Grade, eBioscience (antibody)
RRID:AB_468927
This monoclonal targets CD28
View all literature mentionsCD62L (L-Selectin) Monoclonal Antibody (DREG-56 (DREG56)), APC, eBioscience (antibody)
RRID:AB_10671132
This monoclonal targets CD62L (L-Selectin)
View all literature mentionsTCR beta Monoclonal Antibody (H57-597), PE, eBioscience (antibody)
RRID:AB_466066
This monoclonal targets TCR beta
View all literature mentionsBiotin anti-mouse CD28 (antibody)
RRID:AB_312869
This monoclonal targets CD28
View all literature mentionsAnti-Zap-70, phospho (Tyr319) / Syk, phospho (Tyr352) Antibody, Unconjugated (antibody)
RRID:AB_331600
This unknown targets Zap-70, phospho (Tyr319) / Syk, phospho (Tyr352)
View all literature mentionsPhospho-PLCgamma1 (Tyr783) Antibody (antibody)
RRID:AB_330855
This polyclonal targets Phospho-PLCgamma1 (Tyr783)
View all literature mentionsAnti-mouse IgG, HRP-linked Antibody (antibody)
RRID:AB_330924
This polyclonal targets IgG
View all literature mentionsAnti-rabbit IgG, HRP-linked Antibody (antibody)
RRID:AB_2099233
This polyclonal secondary targets IgG
View all literature mentionsPE anti-human CD197 (CCR7) (antibody)
RRID:AB_10916391
This monoclonal targets CD197
View all literature mentionsBrilliant Violet 421(TM) anti-human CD279 (PD-1) (antibody)
RRID:AB_10960742
This monoclonal targets CD279
View all literature mentionsPE/Cyanine7 anti-human CD223 (LAG-3) (antibody)
RRID:AB_2629753
This monoclonal targets CD223
View all literature mentionsBrilliant Violet 785(TM) anti-mouse CD25 (antibody)
RRID:AB_2564131
This monoclonal targets CD25
View all literature mentionsUltra-LEAF(TM) Purified anti-mouse CD28 (antibody)
RRID:AB_11147170
This monoclonal targets CD28
View all literature mentionsPE/Cyanine7 anti-human/mouse/rat CD278 (ICOS) (antibody)
RRID:AB_10643411
This monoclonal targets CD278
View all literature mentionsBiotin anti-mouse CD3epsilon (antibody)
RRID:AB_312669
This monoclonal targets CD3epsilon
View all literature mentionsUltra-LEAF(TM) Purified anti-mouse CD3epsilon (antibody)
RRID:AB_11149115
This monoclonal targets CD3epsilon
View all literature mentionsBrilliant Violet 421(TM) anti-mouse TCR beta chain (antibody)
RRID:AB_2562562
This monoclonal targets TCR beta chain
View all literature mentionsPE Mouse Anti-TCF-7/TCF-1 Antibody (antibody)
RRID:AB_2687845
This monoclonal targets TCF-7/TCF-1
View all literature mentionsPacific Blue(TM) anti-human CD4 (antibody)
RRID:AB_1595438
This monoclonal targets CD4
View all literature mentionsZAP70 antibody [E267] (antibody)
RRID:AB_778968
This monoclonal targets ZAP70
View all literature mentionsCD3 zeta (phospho Y142) antibody [EP265(2)Y] (antibody)
RRID:AB_11156649
This monoclonal targets CD3 zeta (phospho Y142) antibody [EP265(2)Y]
View all literature mentionsC57BL/6-Tg(TcraTcrb)1100Mjb/J (organism)
RRID:IMSR_JAX:003831
Mus musculus with name C57BL/6-Tg(TcraTcrb)1100Mjb/J from IMSR.
View all literature mentions
