title: Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus.
abstract: There is an urgent need to develop novel therapies for controlling chronic virus infections in immunocompromised patients. Disease associated with persistent γ-herpesvirus infection (EBV, human herpesvirus 8) is a significant problem in AIDS patients and transplant recipients, and clinical management of these conditions is difficult. Immune surveillance failure followed by γ-herpesvirus recrudescence can be modeled using murine γ-herpesvirus (MHV)-68 in mice lacking CD4(+) T cells. In contrast with other chronic infections, no obvious defect in the functional capacity of the viral-specific CD8(+) T cell response was detected. We show in this article that adoptive transfer of MHV-68-specific CD8(+) T cells was ineffective at reducing the viral burden. Together, these indicate the potential presence of T cell extrinsic suppressive factors. Indeed, CD4-depleted mice infected with MHV-68 express increased levels of IL-10, a cytokine capable of suppressing the function of both APCs and T cells. CD4-depleted mice developed a population of CD8(+) T cells capable of producing IL-10 that suppressed viral control. Although exhibiting cell surface markers indicative of activation, the IL-10-producing cells expressed increased levels of programmed death-1 but were not enriched in the MHV-68-specific compartment, nor were they uniformly CD44(hi). Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent virus. These data implicate IL-10 as a promising target for the restoration of immune surveillance against chronic γ-herpesvirus infection in immunosuppressed individuals.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Molloy
authors.forename: Weijun
authors.initials: W
authors.lastname: Zhang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Usherwood
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D018142:Gammaherpesvirinae / Q000276:immunology* / Q000502:physiology; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053701:Receptors, Interleukin-10 / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D016207:Cytokines; D053701:Receptors, Interleukin-10; D016753:Interleukin-10