Measles continues to be an important cause of childhood mortality in developing countries. Measles virus (MV) is lymphotropic and infects high percentages of B-and T-lymphocytes in lymphoid tissues. Cellular immunity is considered crucial for viral clearance; however, MV-specific T-lymphocytes generated during primary infection also constitute a potential target for MV infection. We therefore aimed to identify T-lymphocyte subsets that can clear MV infection without becoming infected. To this end, we infected human EBV transformed B-lymphoblastic cell lines (B-LCL) with a recombinant MV strain expressing enhanced GFP, and co-cultured these with non-infected B-LCL resulting in rapid viral spread. MV-specific CD8 1 T-cell clones efficiently suppressed MV dissemination in autologous and HLA-matched, but not in HLA-mismatched B-LCL. In contrast, CD41 T-cell clones could not control MV dissemination but became a target for MV infection themselves. Furthermore, PBMC collected 6-9 months after acute measles and stimulated with autologous MV-infected B-LCL also efficiently suppressed MV dissemination; this was mediated by the fraction containing CD8 1 T-lymphocytes. In conclusion, we have developed a powerful tool to study cellular immunity against measles, and demonstrate that control of MV dissemination is mediated by virus-specific CD8 1 rather than by CD4 1 T-lymphocytes.Key words: Clearance . Measles virus . Suppression . T-lymphocytes
IntroductionDespite significant progress of global control programs, measles continues to be an important cause of morbidity and mortality in developing countries. Measles virus (MV) is a highly contagious agent that is transmitted by aerosols or direct contact with contaminated respiratory secretions. Measles starts with a prodromal phase of fever, cough and coryza, followed by a generalized maculopapular skin rash and conjunctivitis [1]. This phase is associated with a transient but profound immune suppression that can persist for months after convalescence, resulting in an increased susceptibility to opportunistic infections.Paradoxically, measles also induces strong MV-specific humoral and cellular immune responses, resulting in lifelong immunity [2]. Virus neutralizing serum antibodies are considered the main correlate of protection against MV infection [3]. However, viral clearance is predominantly mediated by cellular immune responses. This is illustrated by the fact that hypogammaglobulinemic children recover normally from MV infection [4,5], whereas children with deficits in cellular immunity develop severe disease and display prolonged viral shedding [4,6,7]. This could be partly due to the spread of MV via cell-cell fusion, thus potentially avoiding neutralizing antibodies in the bloodstream.
Ex vivo experiments have shown that CD81 MV-specific Currently, most studies on antiviral cellular immunity focus on quantification of virus-specific T cells rather than on the functional capacity of these cells. These assays either assess lymphoproliferation (e.g. CFSE dilution assay...