TY - JOUR
T1 - Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism
AU - Arbore, Giuseppina
AU - West, Erin E.
AU - Rahman, Jubayer
AU - Le Friec, Gaelle
AU - Niyonzima, Nathalie
AU - Pirooznia, Mehdi
AU - Tunc, Ilker
AU - Pavlidis, Polychronis
AU - Powell, Nicholas
AU - Li, Yuesheng
AU - Liu, Poching
AU - Servais, Aude
AU - Couzi, Lionel
AU - Fremeaux-Bacchi, Veronique
AU - Placais, Leo
AU - Ferraro, Alastair
AU - Walsh, Patrick R.
AU - Kavanagh, David
AU - Afzali, Behdad
AU - Lavender, Paul
AU - Lachmann, Helen J.
AU - Kemper, Claudia
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.
AB - The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.
UR - http://www.scopus.com/inward/record.url?scp=85054762660&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06706-z
DO - 10.1038/s41467-018-06706-z
M3 - Journal articles
C2 - 30305631
AN - SCOPUS:85054762660
SN - 1751-8628
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4186
ER -