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

Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19

“…In this regard, it is notable that persistent secretion of type I and type III interferon and activated naïve T cells have been reported in patients with post-COVID-19 syndrome [ 78 ] and it will be interesting to determine if such patients have persistent expansion of interferon-activated naïve CD4 + and CD8 + T cells. Interferon activation of naïve CD8 + T cells have been postulated to enhance their homing, survival, differentiation, antiviral and antibacterial effector functions [ 79 , 80 ]. Importantly, clonal tracking revealed that interferon-activated CD4 + T cells were the precursors of TEM in children and CD4 + early memory T cells in adults.…”

After virus exposure, early bystander naïve CD8 T cell activation relies on NAD+ salvage metabolism

“…We first gated on live cells followed by sequential gating on single cells, lymphocytes and CD3+CD8+ T cells to identify 4 subsets of CD8 T cells- naïve, central memory, effector memory, and CD44lowCD62Llow- using CD44 and CD62L as shown in the representative dot plots ( Figure 1A ). The Ly6 family of proteins including Ly6C and Ly6A/E (Sca-1) are important early indicators of bystander activation ( 6 , 27 ). We observed that Ly6C was upregulated in CD44lowCD62L+ naïve CD8 T cells within 24 hours of virus exposure ( Figures 1B, C ).…”

“…Some studies have demonstrated that bystander activation during chronic virus exposure can drive naïve CD8 T cells with memory-like phenotype ( 4 ) or cause them to differentiate into memory-like T cells upon late priming ( 5 ). Interestingly, infections and inflammation driven by the cohousing of laboratory mice with pet store mice can activate naïve CD8 T cells in a bystander manner and impact their homeostasis and function ( 6 ). Type I interferons are rapidly produced early in infection in response to viral exposure.…”

Clonal dynamics of SARS-CoV-2-specific T cells in children and adults with COVID-19

“…In this regard, it is notable that persistent secretion of type I and type III interferon and activated naïve T cells have been reported in patients with post-COVID-19 syndrome (Phetsouphanh et al, 2022) and it will be interesting to determine if such patients have persistent expansion of interferon-activated naïve CD4 + and CD8 + T cells. Interferon activation of naïve CD8 + T cells have been postulated to enhance their homing, survival, differentiation, antiviral and antibacterial effector functions (Jergovic et al, 2021; Urban et al, 2016). Importantly, clonal tracking revealed that interferon-activated CD4 + T cells were the precursors of TEM in children and CD4 + early memory T cells in adults.…”