A novel virus carrier state to evaluate immunotherapeutic regimens: regulatory T cells modulate the pathogenicity of antiviral memory cells.
Restrictions in the diversity of an adaptive immune repertoire can facilitate viral persistence. Because a host afflicted with an immune deficiency is not likely to purge a persistent infection using endogenous mechanisms, it is important to explore adoptive therapies to supplement the host with a functional immune defense. In this study, we describe a virus carrier state that results from introducing lymphocytic choriomeningitis virus (LCMV) into adult mice possessing a restricted T cell repertoire. On infection of these mice, LCMV establishes systemic persistence, and within the CNS the virus infects astrocytes (and later oligodendrocytes) rather than its traditional parenchymal target neurons. To determine whether LCMV could be purged from a novel target selection in the absence of an endogenous immune repertoire, we adoptively transferred virus-specific memory cells into adult carrier mice. The memory cells purged virus from the periphery as well as the CNS, but they induced fatalities not typically associated with adoptive immunotherapy. When the repertoire of the recipient mice was examined, a deficiency in natural regulatory T cells was noted. We therefore supplemented carrier mice with regulatory T cells and simultaneously performed adoptive immunotherapy. Cotransfer of regulatory T cells significantly reduced mortality while still permitting the antiviral memory cells to purge the persistent infection. These data indicate that regulatory T cells can be used therapeutically to lessen the pathogenicity of virus-specific immune cells in an immunodeficient host. We also propose that the novel carrier state described herein will facilitate the study of immunotherapeutic regimens.
Truong
Phi
P
Department of Immunology, Harold L Dorris Neurological Research Institute, Scripps Research Institute, La Jolla, CA 92037, USA.
McGavern
Dorian B
DB
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002353:Carrier State; D002460:Cell Line; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology* / Q000821:virology; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000628:therapy; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009836:Oligodendroglia / Q000166:cytology / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication