Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells

Mladen Jergović, Christopher P. Coplen, Jennifer L. Uhrlaub, David G. Besselsen, Shu Cheng, Megan J. Smithey and Janko Nikolich-Žugich ()
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Mladen Jergović: University of Arizona College of Medicine
Christopher P. Coplen: University of Arizona College of Medicine
Jennifer L. Uhrlaub: University of Arizona College of Medicine
David G. Besselsen: University Animal Care, University of Arizona
Shu Cheng: University of Arizona College of Medicine
Megan J. Smithey: University of Arizona College of Medicine
Janko Nikolich-Žugich: University of Arizona College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.

Date: 2021
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DOI: 10.1038/s41467-021-25645-w

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