Interplay between Virus-Specific Effector Response and Foxp3+ Regulatory T Cells in Measles Virus Immunopathogenesis

Abstract

Measles is a highly contagious childhood disease associated with an immunological paradox: although a strong virus-specific immune response results in virus clearance and the establishment of a life-long immunity, measles infection is followed by an acute and profound immunosuppression leading to an increased susceptibility to secondary infections and high infant mortality. In certain cases, measles is followed by fatal neurological complications. To elucidate measles immunopathology, we have analyzed the immune response to measles virus in mice transgenic for the measles virus receptor, human CD150. These animals are highly susceptible to intranasal infection with wild-type measles strains. Similarly to what has been observed in children with measles, infection of suckling transgenic mice leads to a robust activation of both T and B lymphocytes, generation of virus-specific cytotoxic T cells and antibody responses. Interestingly, Foxp3+CD25+CD4+ regulatory T cells are highly enriched following infection, both in the periphery and in the brain, where the virus intensively replicates. Although specific anti-viral responses develop in spite of increased frequency of regulatory T cells, the capability of T lymphocytes to respond to virus-unrelated antigens was strongly suppressed. Infected adult CD150 transgenic mice crossed in an interferon receptor type I-deficient background develop generalized immunosuppression with an increased frequency of CD4+CD25+Foxp3+ T cells and strong reduction of the hypersensitivity response. These results show that measles virus affects regulatory T-cell homeostasis and suggest that an interplay between virus-specific effector responses and regulatory T cells plays an important role in measles immunopathogenesis. A better understanding of the balance between measles-induced effector and regulatory T cells, both in the periphery and in the brain, may be of critical importance in the design of novel approaches for the prevention and treatment of measles pathology.

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

“…Brain slices were prepared from SLAM ϫ IFNAR ko mice (35) and maintained in culture as detailed previously (30). Briefly, hippocampi were isolated from the brains of 9-day-old mice and cut with a McIlwain tissue chopper (WPI-Europe) to obtain 350-m-thick progressive slices.…”

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

“…SLAM tg mice crossed in an alpha/beta interferon (IFN-␣/␤) receptor (IFNAR)-deficient background; SLAM ϫ IFNAR mice (55,56) were bred at the institute's animal facility (PBES, ENS-Lyon) as heterozygotes for SLAM transgenes. Mice were infected i.n.…”

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…Our results indicate that MV-H interaction with CD150 expressing DC could play an important role in these immunosuppressive consequences of MV infection. Aberrant maturation of DCs could lead not only to the insufficient stimulation of effector cells, but also favor induction of T regulatory cells, increased in both, measles patients 58 and MV-infected CD150tg mice 59 . It is possible that MV-H-CD150 interaction may be involved in the modulation of other cell types function, like memory T lymphocytes, which are particularly affected by MV infection in macaque model 60 .…”