Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus

Abstract

The potent role of indigenous microbiota in maintaining murine CMV (MCMV)-specific memory T cells, which were measured by multimer staining, was investigated using germfree (GF) mice. When the BALB/c mice bred under specific pathogen-free (SPF) conditions were i.p. infected with 0.2 LD50 of MCMV, high frequencies of CD69+/CD44+ MCMV-specific CD8 T cells were noted in the lungs even at 6–12 mo after infection (11.1 ± 3.2 and 9.8 ± 0.9%, respectively). In contrast, even though the viral load and expression levels of mRNA of such cytokines as IL-2, IL-7, IL-15, and IFN-γ in the lungs of MCMV-infected GF mice were comparable to those of infected SPF mice, the frequencies of MCMV-specific CD8 T cells in the lungs of infected GF mice were kept lower than 1% at 6–12 mo after infection. In addition, the reconstitution of microbiota of MCMV-infected GF mice by orally administering a fecal suspension prepared from SPF mice restored the frequencies of both CD8+/multimer+ and CD8+/multimer− T cells to levels similar to those found in SPF mice. These results suggested the indigenous microbiota to play a crucial role in the expansion and maintenance of viral-specific CD8 memory T cells, probably by cross-reactivity between the antigenic epitope of the MCMV-specific memory T cells and the variety of peptides derived from the members of the microbiota. Such cross-reactivity may thus be a major feature of those cells.

Transient TLR Activation Restores Inflammatory Response and Ability To Control Pulmonary Bacterial Infection in Germfree Mice

“…LPS derived from Gram-negative bacteria induces inflammation, costimulation, and immune priming via activation of TLR4 (9). There was no difference in the expression of TLR4 in splenic leukocytes (CD11b + , CD11c + , B220 + , NK1.1 + , and GR1 + leukocytes) from germfree or conventional mice (data not shown), and it has been shown that there is no difference in TLR expression between lung cells of conventional and germfree animals (36). However, contrary to conventional mice, germfree animals produced little TNF-a, did not die, and produced large amounts of IL-10 following exposure to LPS (7) or pulmonary infection with K. pneumoniae (present results).…”

Maternal Antibiotic Treatment Impacts Development of the Neonatal Intestinal Microbiome and Antiviral Immunity

“…In an adult mouse model of respiratory CMV infection, the microbiota was required to promote viral-specific CD8 + memory T cells (21). Analysis of memory T cell development, expansion, and maintenance, as regulated by the GIT microbiota in other adult infection or infant mouse models, has not been explored.…”

“…In adult mice, transient or permanent alterations in the density and diversity of the GIT microbiota affect the maintenance and function of immune cell populations required for mucosal and systemic immune homeostasis (18)(19)(20)(21). T cell immunity is critical for control and clearance of a viral infection, and antibiotic treatment of adult mice alters antiviral innate and adaptive immunity (22,23).…”

Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

“…Because of the prebiotic capacities of the oligosaccharides tested in this study, it is tempting to speculate that microbial products or composition influences gut and systemic immunity. Studies with germfree, restricted flora or antibiotic-treated mice have shown that commensal microbiota can influence systemic immunity by targeting specific cell types, like plasmacytoid dendritic cells, invariant NKT cells, virus-specific CD8 ϩ memory cells, and marginal-zone B cells (13,51,58,59). Products from gut bacteria provide signals for pattern recognition receptors like NOD or Toll-like receptors.…”