The normal cellular form of the prion protein PrPC is a glycosylphosphatidylinositol-linked cell-surface glycoprotein expressed primarily by cells of the nervous and immune systems. There is evidence to suggest that PrPC is involved in cell signalling and cellular homeostasis. We have investigated the immune composition of peripheral lymphoid tissue in PrP−/−, wild-type,tg19andtga20strains of mice, which express 0, 1-, 3-5- and 4-7-fold higher levels of PrPC, respectively, relative to wild-type mice. Our data show thattga20mice have a reduced number of spleen T-cell receptor (TCR)-αβ+ T cells and an increased number of TCR-γδ+ T cells compared with wild-type mice. This was not seen intg19mice, which also express elevated levels of PrPC. In addition, we have found that thePrnptransgene in thetga20genome is located centrally on chromosome 17, in or around genes involved in T-cell development. Significantly, mRNA transcripts from pre-TCR-α (pTα), a T-cell development gene located on mouse chromosome 17, are drastically reduced intga20mice, indicative of a perturbation inpTαgene regulation. We propose that the immune cell phenotype oftga20mice may be caused by the insertional mutation of thePrnptransgene into thepTαgene or its regulatory elements.