Differential Requirements of CD45 Protein Tyrosine Phosphatase for Cytolytic Activities and Intrathymic and Extrathymic Development of Intestinal Intraepithelial Lymphocytes

Abstract

CD45 is a transmembrane protein tyrosine phosphatase essential for Ag receptor-mediated signaling in both T and B cells. In this study we investigated roles of CD45 in development and cytolytic activities of murine intestinal intraepithelial lymphocytes (i-IEL) using CD45 exon 6 knockout (CD45−/−) mice. Interestingly, the total cell number of i-IEL was significantly reduced in CD45−/− mice during aging (10–20 wk of age), whereas the i-IEL number was normally increased in the wild-type littermates. Especially, the number of γδTCR+ i-IEL decreased markedly in CD45−/− mice during aging. The i-IEL in CD45−/− mice were more susceptible to in vitro spontaneous apoptosis than the normal i-IEL, implying that CD45 is required for maintenance of the cellularity of i-IEL. Results from in vivo analyses of the extrathymic and intrathymic development of i-IEL suggested that CD45-mediated signaling is required for the intrathymic, but not the extrathymic, development of i-IEL. Moreover, the whole i-IEL from CD45−/− mice showed a significantly reduced cytolytic activity, and the residual cytolytic activity was completely diminished by depleting CD45+ i-IEL, suggesting that CD45 is indispensable for the TCR-mediated cytolytic activity of i-IEL. Furthermore, we found differential contributions of CD45 and p56lck to development and induction of cytolytic activities of i-IEL.