Functional Exhaustion Limits CD4+ and CD8+ T-Cell Responses to Congenital Cytomegalovirus Infection

Background. Cytomegalovirus ( CMV) infection during fetal life causes severe symptoms and is associated with prolonged viral excretion. Previous studies reported low CD4(+) T-cell responses to CMV infection in early life, contrasting with large responses of effector CD8(+) T cells. The mechanisms underlying the defective CD4(+) T-cell responses and the possible dissociation with CD8(+) T-cell responses have not been clarified. Methods. The magnitude and the quality of the fetal CD8(+) and CD4(+) T-cell responses to CMV infection were compared to those of adults with primary or chronic infection. Results. In utero CMV infection induced oligoclonal expansions of fetal CD4(+) and CD8(+) T lymphocytes expressing a T-helper type 1 or Tc1 effector phenotype similar to that of adult CMV-specific cells. However, the effector cytokine responses and the polyfunctionality of newborn CD4(+) and CD8(+) T cells were markedly lower than those of adult cells. This reduced functionality was associated with a higher expression of the programmed death 1 inhibitory receptor, and blockade of this receptor increased newborn T-cell responses. Conclusions. Functional exhaustion limits effector CD4(+) and CD8(+) T-lymphocyte responses to CMV during fetal life.