Perturbation of T-cell development by insertional mutation of a PrP transgene.
The normal cellular form of the prion protein PrP(C) is a glycosylphosphatidylinositol-linked cell-surface glycoprotein expressed primarily by cells of the nervous and immune systems. There is evidence to suggest that PrP(C) is involved in cell signalling and cellular homeostasis. We have investigated the immune composition of peripheral lymphoid tissue in PrP-/-, wild-type, tg19 and tga20 strains of mice, which express 0, 1-, 3-5- and 4-7-fold higher levels of PrP(C), respectively, relative to wild-type mice. Our data show that tga20 mice have a reduced number of spleen T-cell receptor (TCR)-alphabeta(+) T cells and an increased number of TCR-gammadelta(+) T cells compared with wild-type mice. This was not seen in tg19 mice, which also express elevated levels of PrP(C). In addition, we have found that the Prnp transgene in the tga20 genome is located centrally on chromosome 17, in or around genes involved in T-cell development. Significantly, mRNA transcripts from pre-TCR-alpha (pTalpha), a T-cell development gene located on mouse chromosome 17, are drastically reduced in tga20 mice, indicative of a perturbation in pTalpha gene regulation. We propose that the immune cell phenotype of tga20 mice may be caused by the insertional mutation of the Prnp transgene into the pTalpha gene or its regulatory elements.
Zabel
Mark
M
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, USA.
Greenwood
Christina
C
Thackray
Alana M
AM
Pulford
Bruce
B
Rens
Willem
W
Bujdoso
Raymond
R
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003208:Concanavalin A / Q000276:immunology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019076:Transgenes
D011328:Prions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D003208:Concanavalin A