STING controls T cell memory fitness during infection through T cell intrinsic and IDO dependent mechanisms
Quaney, M.J. et al. (BioRxiv) doi: 10.1101/2022.03.19.484992
CD8 T cell memory
STING is an innate sensor that plays a role in many branches of both normal and dysregulated immune responses. While T cells are known to express STING, the interplay between STING activation and antigenic strength in the context of T cell memory generation has not been previously explored. Quaney et al show that T cell intrinsic STING signalling impairs generation of CD8 memory by promoting the unfolded protein response and apoptosis. This outcome is dependent on TCR affinity for its cognate antigen upon initial stimulation ofnaïveCD8 T cells. CD8 T cells with high affinity TCRs are highly susceptible to apoptosis during the contraction phase–however–CD8 T cells with low affinity TCRs can survive to generate functional memory T cells. This phenomenon may have a protective function for the organism by aiding the homeostasis of the immune response. The group also demonstrates that blockade of IDO, an enzyme commonly elevated in the context of chronic inflammation that catabolizes indole ring-containing compounds, protects antigen-specific CD8 T cells from the pro-apoptotic effects of STING signalling.
Mechanistic linkage between TCR affinity and differential responses to STING signalling not shown.
Functional characterization of CD8 memory T cells not shown for experiments utilizing IDO blockade. Although the numbers of antigen-specific CD8memory T cells are rescued, it is important to know whether they are functionally identical to CD8 memory T cells generated in the absence of STING signalling.
Detailed phenotypic comparisons of low and high affinity CD8 memory T cells generated in STINGhi and WT conditions would have been a nice complement to the functional studies shown in the supplement.
Cyclic-di-AMP is a potent stimulator of murine STING but not of human STING–it would be compelling to see evidence of the translatability of the group’s findings to humans.
Quaney et al are the first to show that activation of the STING pathway in high affinity CD8 T cells can impair the generation of memory T cells.
The findings from this preprint have implications for translational applications that target STING, including vaccine design(adjuvants)and cancer immunotherapies. If these findings also apply to humans, it may be beneficial to avoid the use of potent or broadly-acting STING agonists in contexts where high affinity epitopes may be generated (e.g. cancers with high mutation burden, certain vaccines), in order to preserve a functional CD8 T cell memory response. Furthermore, the findings from this preprint may provide an explanation for the observed discrepancy of T cell cytopenia and autoimmunity in patients with STING gain of function mutations.
Reviewed by Yonina Bykov as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.