Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells

Measles virus (MV) infection induces a profound immunosuppression responsib le for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DCs) in the respiratory mucosa or in the secondary l ymphoid organs, The purpose of this study was to investigate the consequenc es of DC infection by MV, particularly concerning their maturation and thei r ability to generate CD8(+) T cell proliferation. We first show that MV-in fected Langerhans cells or monocyte-derived DCs undergo a maturation proces s similarly to the one induced by TNF-alpha or LPS, respectively. CD40 liga nd (CD40L) expressed on activated T cells is shown to induce terminal diffe rentiation of DCs into mature effector DCs, In contrast, the CD40L-dependen t maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression down-regulation. Moreover , the CD40L-induced cytokine pattern in DCs is modified by MV infection wit h inhibition of IL-12 and IL-1 alpha/beta and induction of IL-10 mRNAs synt hesis. Using peripheral blood lymphocytes from CD40L-deficient patients, we demonstrate that MV infection of DCs prevents the CD40L-dependent CD8(+) T cell proliferation. In such DC-PBL cocultures, inhibition of CD80 and CD86 expression on DCs was shown to require both MV replication and CD40 trigge ring, Finally, for the first time, MV was shown to inhibit tyrosine-phospho rylation level induced by CD40 activation in DCs, Our data demonstrate that MV replication modifies CD40 signaling in DCs, thus leading to impaired ma turation, This phenomenon could play a pivotal role in MV-induced immunosup pression.