Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life.

Terhi Ruohtula,Janne K Nieminen,Onni Niemelä,The Diabimmune Study Group ,Jorma Ilonen,Anita Kondrashova,Outi Vaarala,Vallo Tillmann,Aleksandr Peet,Heikki Hyöty,Mikael Knip,Anu-Maaria Hämäläinen,Sami Oikarinen,Jussi Lehtonen

doi:10.3389/fimmu.2020.567046

Abstract

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127−/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.

Highlights

The immune system maturates rapidly during the first year of life
Our results suggest that rhinovirus and enterovirus infections modulate FOXP3 expression and Treg maturation differently during the first year of life: enterovirus decreases the FOXP3 expression while rhinovirus may increase FOXP3 expression
We found that the infants with preceding rhinovirus infection showed lower levels of several cytokines in comparison to those without preceding viral infections

Summary

Introduction

The immune system maturates rapidly during the first year of life. The immunological pathways that mediate the pathogenesis of immune-mediated diseases are often programmed during this period. FOXP3-expressing regulatory T cells (Tregs) play crucial roles in maintaining tolerance to self-antigens and in regulating excessive inflammation in infectious diseases. They comprise 1%–10% of thymic and peripheral CD4+ T cells. It is well established that microbes can induce Tregs (iTregs), which may play a key role in the regulation of harmful immune responses. Viral infections have potent effects on cytokine production, influence T cell differentiation, and induce a broad range of iTreg subsets. Virus-induced Tregs are generally antigen-specific, inhibit proliferation and cytokine production of CD4+ and CD8+ T cells, and affect the maturation of dendritic cells, activation of natural killer cells, and immunoglobulin production of B cells [2, 3]. The regulatory effects of CD8+ T cells have mainly been associated with chronic, persistent infectious diseases such as leprosy, HIV, Epstein-Barr virus, hepatitis C, and tuberculosis [8,9,10,11,12]

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