To understand the natural history of immune responses centering CD4+ T cells at genetic level during experimental infection with Schistosoma japonicum (S. japonicum), the mRNA profiles of CD4+ T cells from spleens of mice at 0, 3, 6, and 13 weeks after the onset of the infection, were compared using mouse oliogonucleotide microarrays (Affymetrix GeneChip U74A). Of about 12,000 mouse probe sets in a microarray, nearly 10% encoded a variety of immune regulators, including many cytokine and chemokine genes, immunoglobulin-related genes, and genes related to apoptosis and the stress response. These changed in transcript representation as the schistosome infection progressed, and a key finding, which was validated by semi-quantitative PCR, was that a significant portion of the genes which were down-regulated as infection progressed coded for interferon (IFN)-inducible molecules, including GTPases, transcription factors and chemokines. The results thus showed that there is a characteristic change in IFN-inducible gene expression over the course of the schistosome infection, and it is suggested that the IFN-gamma-regulated GTPase family may be involved in IFN-mediated resistance against S. japonicum.