DIFFERENTIAL CONTRIBUTION OF LCK AND FYN PROTEIN-TYROSINE KINASES TO INTRAEPITHELIAL LYMPHOCYTE DEVELOPMENT

The developmental stages and the role of protein tyrosine kinases (PTK ) in the maturation of CD3(+)CD8 alpha alpha(+) intraepithelial lympho cytes (IEL) have not been extensively characterized. However, comparis ons of thymic and extrathymic T cell development indicate that these p rocesses involve some distinct signaling and selection events. We used mice deficient in Lck, Fyn, or both Lck and Fyn to analyze the role t hat these src-family PTK play in IEL development. In contrast to thymo cyte development, we found that all IEL subsets develop in mice defici ent for either kinase alone. However, lck(-/-) animals exhibited reduc ed numbers of TcR alpha beta(+)CD8 alpha alpha(+) IEL, indicating that Lck is important in the development of these cells. Mice which lack b oth Lck and Fyn fail to generate TcR alpha beta(+) IEL, suggesting tha t signaling through the preTcR, mediated by Lck and, to a lesser exten t Fyn, is required for maturation of all TcR alpha beta(+) IEL lineage s. Interestingly, a small population of TcR gamma delta(+)CD8 alpha al pha(+) cells are apparent in lck(-/-)fyn(-/-) animals, demonstrating t hat TcR alpha beta(+)CD8 alpha alpha(+) and TcR gamma delta(+)CD8 alph a alpha(+) IEL have distinct PTK requirements for their development or expansion. CD3(-)-CD8 alpha(-)CD44(+) and CD3(-)CD8 alpha alpha(+)CD1 6/32(+)B220(+) cells comprise the majority of IEL in both lck(-/-)fyn( -/-) and rag(-/-) mice, while they are poorly represented in wild-type controls. Comparison of the cell surface phenotype of these putative precursor IEL in lck(-/-)fyn(-/-) and rag(-/-) animals suggests that I EL maturation in these animals is arrested at an equivalent developmen tal stage. Overall, the data presented demonstrate that signals mediat ed by Lck or Fyn direct TcR alpha beta(+)CD8 alpha alpha(+) IEL matura tion but are dispensable for the development of TcR gamma delta(+)CD8 alpha alpha(+) IEL.