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.
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
Since the mechanisms by which specific immunity destroys Her-2/neu carcinoma cells are highly undetermined, these were assessed in BALB/c mice vaccinated with plasmids encoding extracellular and transmembrane domains of the protein product (p185neu) of the rat Her-2/neu oncogene shot into the skin by gene gun. Vaccinated mice rejected a lethal challenge of TUBO carcinoma cells expressing p185neu. Depletion of CD4 T cells during immunization abolished the protection, while depletion of CD8 cells during the effector phase halved it, and depletion of polymorphonuclear granulocytes abolished all protection. By contrast, Ig μ-chain gene KO mice, as well as Fcγ receptor I/III, β-2 microglobulin, CD1, monocyte chemoattractant protein 1 (MCP1), IFN-γ, and perforin gene KO mice were protected. Only mice with both IFN-γ and perforin gene KOs were not protected. Although immunization also cured all BALB/c mice bearing established TUBO carcinomas, it did not cure any of the perforin KO or perforin and IFN-γ KO mice. Few mice were cured that had knockouts of the gene for Ig μ-chain, Fcγ receptor I/III, IFN-γ, or β-2 microglobulin. Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185neu carcinomas involves distinct mechanisms, each endowed with a different curative potential.
Claudia Curcio, Emma Di Carlo, Raphael Clynes, Mark J. Smyth, Katia Boggio, Elena Quaglino, Michela Spadaro, Mario P. Colombo, Augusto Amici, Pier-Luigi Lollini, Piero Musiani, Guido Forni
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