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,Janko Nikolich-Žugich

doi:10.1038/s41467-021-25645-w

Mladen Jergović, Christopher P Coplen + Show 5 more

Open Access

https://doi.org/10.1038/s41467-021-25645-w

Copy DOI

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.

Highlights

Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation
Seminal findings of Suhr, Sprent, and colleagues have shown that Tn cells require tonic, subthreshold T cell receptor (TCR) stimulation by self-peptide:MHC (s-pMHC), followed by binding of lymph node stromaproduced IL-7 to the IL-7 receptor (IL-7R), for survival and maintenance, as well as for homeostatic proliferation[4]
Authors found that specific pathogen-free (SPF) mice exhibited T cell subset distribution and activation patterns similar to that of human neonates, whereas the same parameters in wild-caught, pet-store, or inbred SPF mice cohoused with pet stores (PS) mice, faithfully approximated the distribution of T cell subsets, T cell subset activation and responses to infection seen in adult humans

Summary

Introduction

Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. 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. Seminal findings of Suhr, Sprent, and colleagues have shown that Tn cells require tonic, subthreshold T cell receptor (TCR) stimulation by self-peptide:MHC (s-pMHC), followed by binding of lymph node stromaproduced IL-7 to the IL-7 receptor (IL-7R), for survival and maintenance, as well as for homeostatic proliferation[4] These and almost all other studies on Tn homeostasis were done in inbred mice housed under specific pathogen-free (SPF) or even germfree or antigen-free[5] conditions, in the almost complete absence of infection and inflammation. Our results demonstrate a novel and powerful role of infection-mediated IFN-I in CD8+ Tn homeostasis

Methods

Results

Conclusion