During the early postnatal period lymphocytes migrate into the mouse small intestine. Migrating infiltrative lymphocytes have the potential to affect the epithelial cells via secreted cytokines. Such cross talk can result in the elicitation of an epithelial transcriptional response. Knowledge about such physiological cross talk between the immune system and the epithelium in the postnatal small intestinal mucosa is lacking. We have investigated the transcriptome changes occurring in the postnatal mouse small intestine using DNA microarray technology, immunocytochemistry, and quantitative real-time RT-PCR analysis. The DNA microarray data were analyzed bioinformatically by using a combination of projections to latent structures analysis and functional annotation analysis. The results show that infiltrating lymphocytes appear in the mouse small intestine in the late postweaning period and give rise to distinct changes in the epithelial transcriptome. Of particular interest is the expression of three genes encoding a mucin (Muc4), a mucinlike protein (16000D21Rik), and ATP citrate lyase (Acly). All three genes were shown to be expressed by the epithelium and to be upregulated in response to lymphocytic migration into the small intestinal mucosa.