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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., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)