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

J Infect Dis. 2015 Aug 1;212(3):484-94. doi: 10.1093/infdis/jiv071. Epub 2015 Feb 5.


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.

Keywords: CD4 T cell; CD8 T cell; congenital infection; cytomegalovirus; exhaustion; fetus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Viral / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cohort Studies
  • Cytokines / blood
  • Cytokines / immunology
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / congenital*
  • Cytomegalovirus Infections / immunology*
  • Female
  • Fetal Blood / cytology
  • Humans
  • Infant, Newborn
  • Pregnancy
  • Pregnancy Complications, Infectious / immunology*


  • Antigens, Viral
  • Cytokines