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Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus¹

Kazuo Tanaka^2,*, Sadaaki Sawamura^*, Tadayuki Satoh, Kiyoshi Kobayashi^* and Satoshi Noda^*

^* Laboratory of Infectious Diseases and Teaching and Research Supporting Center, Tokai University School of Medicine, Isehara, Kanagawa, Japan

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to K.T.) (14571159 and 17591349).

² Address correspondence and reprint requests to Dr. Kazuo Tanaka, Laboratory of Infectious Diseases, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan. E-mail address: tanakaka{at}is.icc.u-tokai.ac.jp

³ Abbreviations used in this paper: MCMV, murine CMV; Ct, cycle threshold; GF, germfree; IE, immediate early; IE1, IE-protein 1; MLN, mesenteric lymph node; SPF, specific pathogen free.