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 5

CD4+ T cell STING is required for Tr1 cell development in experimental malaria.

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CD4+ T cell STING is required for Tr1 cell development in experimental m...
(A) 5 × 105 CD45.2+ PbTIIΔSting and 5 × 105 CD45.1+ CD45.2+ PbTIIWT cells were transferred into the Ptprca (CD45.1+) recipient mice at day –1. The mice were infected with P. berghei ANKA (PbA) on day 0 and were assessed on day 4. (B) Representative histograms and enumeration showing the IL-10– and IFN-γ–producing PbTIIWT and PbTIIΔSting cells. (C and D) Representative plots and enumeration showing the frequencies of IL-10+IFN-γ+ and LAG3+CD49b+ CD4+ T cells, respectively. Data in each plot were pooled from 3 independent experiments. Lines connect paired samples, and box shows extent of lower and upper quartiles plus median, while whiskers indicate minimum and maximum data points. n = 24. Two-tailed paired t test. ***P < 0.001; ****P < 0.0001.