STING activation promotes autologous type I interferon–dependent development of type 1 regulatory T cells during malaria
Yulin Wang, … , Michelle J. Boyle, Christian R. Engwerda
Yulin Wang, … , Michelle J. Boyle, Christian R. Engwerda
Published October 2, 2023
Citation Information: J Clin Invest. 2023;133(19):e169417. https://doi.org/10.1172/JCI169417.
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Research Article Infectious disease

STING activation promotes autologous type I interferon–dependent development of type 1 regulatory T cells during malaria

Abstract

The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10– and IFN-γ–coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.

Authors

Yulin Wang, Fabian De Labastida Rivera, Chelsea L. Edwards, Teija C.M. Frame, Jessica A. Engel, Luzia Bukali, Jinrui Na, Susanna S. Ng, Dillon Corvino, Marcela Montes de Oca, Patrick T. Bunn, Megan S.F. Soon, Dean Andrew, Jessica R. Loughland, Jia Zhang, Fiona H. Amante, Bridget E. Barber, James S. McCarthy, J. Alejandro Lopez, Michelle J. Boyle, Christian R. Engwerda

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Figure 2

Modulation of CD4+ T cell STING expression by CRISPR/Cas9 gene editing.

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Modulation of CD4+ T cell STING expression by CRISPR/Cas9 gene editing. ...
(A) CD4+ T cells from 8 healthy volunteers were stimulated with αCD3ε and αCD28 mAbs plus IL-2 for 72 hours before nucleofection and then stimulated for another 72 hours under the same conditions. Cells were treated with or without cGAMP for 18 hours before analysis. (B) A diagram showing the gene structure of human TMEM173 and the CRISPR gRNA–targeting sites within exon 4. Domain structure of the human STING protein showing the 4 transmembrane domains of the N-terminal, responsible for ligand binding and protein dimerization. The C-terminal contains the cyclic dinucleotide domain and binding sites for TBK1 and IRF3. (C) qPCR validation of TMEM173 mRNA expression in control and CRISPR gRNA–treated samples. TMEM173 mRNA was normalized to 18S rRNA in each sample. Data were log2-transformed for statistical analysis. Lines connect paired samples, and box shows the extent of lower and upper quartiles plus median, while whiskers indicate minimum and maximum data points. n = 8 samples. Two-tailed paired t test. ***P < 0.001. (D) Representative Western blot showing the effect of CRIPSR gRNA modification of TMEM173 in response to cGAMP stimulation, as indicated. β-Actin was used as a protein-loading control, relative to STING protein levels. (E) Representative FACS plots showing loss of STING phosphorylation in control and CRISPR gRNA samples treated, as indicated.