TY - JOUR
T1 - Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis
AU - Ohtsuki, Shozo
AU - Wang, Chenyao
AU - Watanabe, Ryu
AU - Zhang, Hui
AU - Akiyama, Mitsuhiro
AU - Bois, Melanie C.
AU - Maleszewski, Joseph J.
AU - Warrington, Kenneth J.
AU - Berry, Gerald J.
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01AR042527, R01AI108906, R01HL142068, and R01HL117913 to C.M.W. and R01AI108891, R01AG045779, U19AI057266, and R01AI129191 to J.J.G.). Conceptualization, C.M.W. J.J.G. and S.O.; formal analysis, S.O. and C.W.; investigation, S.O. C.W. R.W. H.Z. M.A. and G.J.B.; patient recruitment, C.M.W. J.J.G. S.O. G.J.B. M.C.B. J.J.M. and K.J.W.; writing – original draft, C.M.W. J.J.G. and S.O.; supervision, C.M.W. J.J.G. and G.J.B.; funding acquisition, C.M.W. and J.J.G. K.J.W. has received clinical trial support from Eli Lilly, GSK, and Kiniksa; he received consulting fees and honoraria from Chemocentryx.
Funding Information:
This work was supported by the National Institutes of Health ( R01AR042527 , R01AI108906 , R01HL142068 , and R01HL117913 to C.M.W. and R01AI108891 , R01AG045779 , U19AI057266 , and R01AI129191 to J.J.G.).
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/4/18
Y1 - 2023/4/18
N2 - Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.
AB - Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.
KW - autoimmune vasculitis
KW - autoimmunity
KW - CD155
KW - CD96
KW - ER stress
KW - giant cell arteritis
KW - IL-9
KW - immune checkpoint receptors
KW - macrophage
KW - T cell
UR - http://www.scopus.com/inward/record.url?scp=85152299386&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152299386&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2023.101012
DO - 10.1016/j.xcrm.2023.101012
M3 - Article
C2 - 37075705
AN - SCOPUS:85152299386
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 4
M1 - 101012
ER -
