The aim of our work is to characterise the development of cell-mediated immunity in vivo in humans using congenital infection with cytomegalovirus (CMV) as a model. We previously showed that mature CD8 cytotoxic T lymphocyte responses to CMV can already develop in utero. In contrast, newborns with congenital infection have defective CD4 helper T lymphocyte responses to the virus. Oligoclonal expansions of CD4 T lymphocytes can be detected in infected newborns but these cells neither proliferate nor secrete anti-viral cytokines in response to CMV antigen. The objective of this project is to decipher the response of CD4 helper T cells to congenital CMV infection at the molecular level. As CMV is the only pathogen affecting the T cell repertoire of infected newborns, the influence of the virus on foetal T lymphocytes can be directly inferred from a comparison with the naive T cell repertoire of uninfected control newborns. In order to elucidate the mechanisms involved in their functional defect, the characteristics of CD4 T lymphocytes from CMV-infected newborns are compared to those of their mother. Our results indicate that maternal CD4 T cells rapidly produce anti-viral cytokines following primary CMV infection whereas their capacity to proliferate is acquired only after several months. Our working hypothesis is that CMV interferes with the functions of CD4 T lymphocytes during primary infection and that the consequences of this interference are different in adults and young infants

Principal investigator: Arnaud MARCHANT (MD-PhD)
Associate investigator: Stéphane TEMMERMAN (PhD)
MD-PhD students: Pierre ANTOINE, Nicolas TWITE
PhD student: Ariane HUYGENS
Research assistant: Véronique OLISLAGERS
Technical assistant: Sandra LECOMTE

C. LIESNARD, N. D'HAENE & C. DONNER, Hôpital Erasme, ULB
M. TACKOEN, P. BARLOW & M. VanRysselberge, Hôpital Saint-Pierre, ULB
R. SNOECK & G. ANDREI, Rega Institute, KUL
R. WATTIEZ, Université de Mons-Hainaut

Miles DJC, van der Sande M, Jeffries D, Kaye S, Ojuola O, Sanneh M, Cox M, Palmero MS, Touray ES, Waight P, Rowland-Jones S, Whittle H, Marchant A. Maintenance of large subpopulations of differentiated CD8 T-Cells two years after cytomegalovirus infection in Gambian infants. PLoS ONE 2008; 3: e2905

Kaye S, Miles D, Antoine P, Burny W, Ojuola B, Kaye P, Rowland-Jones S, Whittle H, van der Sande M, Marchant A. Virological and immunological correlates of mother to child transmission of cytomegalovirus in The Gambia. J Infect Dis 2008; 197: 1307-1314

Miles DJ, van der Sande M, Jeffries D, Kaye S, Ismaili J, Ojuola O, Sanneh M, Touray ES, Waight P, Rowland-Jones S, Whittle H, Marchant A. Cytomegalovirus infection in Gambian infants leads to profound CD8 T cell differentiation. J Virol 2007; 81: 5766-5776

Marchant A, Goldman M. T cell-mediated immune responses in human newborns : ready to learn ? Clin Exp Immunol 2005; 141: 10-18

Miles DJC, van der Sande M, Kaye S, Crozier S, Ojuola O, Palmero MS, Sanneh M, Touray ES, Waight P, Rowland-Jones S, Whittle H, Marchant A. CD4 T-cell responses to CMV mature slowly following infection in infancy: a prospective birth cohort study. J Infect Dis 2008; 197: 658-662

Government of the Walloon Region
GSK Biologicals
The Fund for Scientific Research (F.R.S - FNRS) and the Télévie Programme
The Belgian Science Policy
The European Commission
The Erasme Fund The Wiener-Anspach Foundation
The Belgian Kid's Fund
The Roche Organ Transplantation Research Foundation
The Dimitris and Noela Nakos Foundation
Roche Pharmaceuticals, Belgium
Wittycell S.A.S