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

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 CD5^hiCD8⁺ 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.

SUBMITTER: Jergovic M

PROVIDER: S-EPMC8421345 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Jergović Mladen M Coplen Christopher P CP Uhrlaub Jennifer L JL Besselsen David G DG Cheng Shu S Smithey Megan J MJ Nikolich-Žugich Janko J

Nature communications 20210906 1

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 ...[more]

PMID: 34489451

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Project description:BackgroundCD8+ T cells equipped with a full arsenal of antiviral effector functions are critical for effective immune control of HIV-1. It has nonetheless remained unclear how best to elicit such potent cellular immune responses in the context of immunotherapy or vaccination. HIV-2 has been associated with milder disease manifestations and more commonly elicits functionally replete virus-specific CD8+ T cell responses compared with HIV-1. We aimed to learn from this immunological dichotomy and to develop informed strategies that could enhance the induction of robust CD8+ T cell responses against HIV-1.MethodsWe developed an unbiased in vitro system to compare the de novo induction of antigen-specific CD8+ T cell responses after exposure to HIV-1 or HIV-2. The functional properties of primed CD8+ T cells were assessed using flow cytometry and molecular analyses of gene transcription.FindingsHIV-2 primed functionally optimal antigen-specific CD8+ T cells with enhanced survival properties more effectively than HIV-1. This superior induction process was dependent on type I interferons (IFNs) and could be mimicked via the adjuvant delivery of cyclic GMP-AMP (cGAMP), a known agonist of the stimulator of interferon genes (STING). CD8+ T cells elicited in the presence of cGAMP were polyfunctional and highly sensitive to antigen stimulation, even after priming from people living with HIV-1.InterpretationHIV-2 primes CD8+ T cells with potent antiviral functionality by activating the cyclic GMP-AMP synthase (cGAS)/STING pathway, which results in the production of type I IFNs. This process may be amenable to therapeutic development via the use of cGAMP or other STING agonists to bolster CD8+ T cell-mediated immunity against HIV-1.FundingThis work was funded by INSERM, the Institut Curie, and the University of Bordeaux (Senior IdEx Chair) and by grants from Sidaction (17-1-AAE-11097, 17-1-FJC-11199, VIH2016126002, 20-2-AEQ-12822-2, and 22-2-AEQ-13411), the Agence Nationale de la Recherche sur le SIDA (ECTZ36691, ECTZ25472, ECTZ71745, and ECTZ118797), and the Fondation pour la Recherche Médicale (EQ U202103012774). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z).

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

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Infection-induced type I interferons critically modulate the homeostasis and function of CD8<sup>+</sup> naïve T cells.

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

Publications

Infection-induced type I interferons critically modulate the homeostasis and function of CD8<sup>+</sup> naïve T cells.

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OmicsDI is part of the ELIXIR infrastructure

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