Mature CD8+ T lymphocyte response to viral infection during fetal life
Arnaud Marchant, … , Andrew J. McMichael, Hilton Whittle
Arnaud Marchant, … , Andrew J. McMichael, Hilton Whittle
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1747-1755. https://doi.org/10.1172/JCI17470.
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Article

Mature CD8+ T lymphocyte response to viral infection during fetal life

Abstract

Immunization of newborns against viral infections may be hampered by ineffective CD8+ T cell responses. To characterize the function of CD8+ T lymphocytes in early life, we studied newborns with congenital human cytomegalovirus (HCMV) infection. We demonstrate that HCMV infection in utero leads to the expansion and the differentiation of mature HCMV-specific CD8+ T cells, which have similar characteristics to those detected in adults. High frequencies of HCMV-specific CD8+ T cells were detected by ex vivo tetramer staining as early as after 28 weeks of gestation. During the acute phase of infection, these cells had an early differentiation phenotype (CD28–CD27+CD45RO+, perforinlow), and they acquired a late differentiation phenotype (CD28–CD27-CD45RA+, perforinhigh) during the course of the infection. The differentiated cells showed potent perforin-dependent cytolytic activity and produced antiviral cytokines. The finding of a mature and functional CD8+ T cell response to HCMV suggests that the machinery required to prime such responses is in place during fetal life and could be used to immunize newborns against viral pathogens.

Authors

Arnaud Marchant, Victor Appay, Marianne van der Sande, Nicolas Dulphy, Corinne Liesnard, Michael Kidd, Steve Kaye, Olubukola Ojuola, Geraldine M.A. Gillespie, Ana L. Vargas Cuero, Vincenzo Cerundolo, Margaret Callan, Keith P.W.J. McAdam, Sarah L. Rowland-Jones, Catherine Donner, Andrew J. McMichael, Hilton Whittle

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Cytolytic activity and antiviral cytokine production by HCMV-specific CD...
Cytolytic activity and antiviral cytokine production by HCMV-specific CD8+ T cells in HCMV-infected newborns. (a) Expression of perforin and granzyme A by total and HCMV-specific CD8+ T cells from case 2. HCMV-specific CD8+ T cells expressed high levels of perforin and granzyme A. Three levels of perforin expression are shown: negative, low, and high. Similar results were obtained in cases no. 1, 3, and 4. (b) Ex vivo cytolytic activity of HCMV tetramer+ CD8+ T cells from case no. 2. Purified CD8+ T lymphocytes including 7.5% of pp65495-503 peptide-specific cells were incubated with peptide-loaded JY cells at 5:1 tetramer positive cell/target ratio (black bars). An HLA-A2-restricted pp65495-503 peptide-specific clone was used as a positive control at a similar effector/target ratio. HCMV-specific CD8+ T cells had potent cytolytic activity that was dependent on perforin, as demonstrated by inhibition with CMA (white bars). (c) HLA-A2/pp65495-503 tetramer (A2 CMV)+ CD8+ T cells from case no. 2 produce IFN-γ, TNF-α, and MIP-1β, but no IL-2 following short-term peptide restimulation.