CONTROL OF THYMUS-INDEPENDENT INTESTINAL INTRAEPITHELIAL LYMPHOCYTES BY BETA-2-MICROGLOBULIN

Murine intestinal intraepithelial lymphocytes (i-IEL) comprise thymus- dependent cells such as T cell receptor (TcR) alpha/beta CD8 alpha/bet a(+) i-IEL, as well as thymus-independent ones such as TcR alpha/beta CD8 alpha/alpha(+) and TcR gamma/delta CD8 alpha/alpha(+) i-IEL. Whils t the development of the CD8 alpha/beta expressing i-IEL is strictly c ontingent on major histocompatibility complex (MHC) class I surface ex pression, that of CD8 alpha/alpha i-IEL appears largely MHC class I in dependent. We have used beta 2-microglobulin (beta 2m)(-/-) mutant mic e lacking surface-expressed MHC class I and TcR alpha/beta CD8 alpha/b eta(+) i-IEL to analyze the potential impact of MHC class I on regiona l activation of thymus-independent i-IEL. To analyze the role of TcR g amma/delta i-IEL in regional cell interactions, these mice were treate d with the anti-TcR gamma/delta mAb, GL3. Whilst numbers of TcR alpha/ beta CD8 alpha/alpha i-IEL were markedly reduced in beta 2m(-/-) mice, those of TcR gamma/delta i-IEL were elevated. Administration of GL3 i n vivo caused TcR down-modulation and functional inactivation of TcR g amma/delta i-IEL in beta 2m(+/-) mice. In contrast, TcR expression and functional activities of TcR gamma/delta i-IEL from beta 2m(-/-) mice were not impaired by GL3 treatment. The TcR alpha/beta CD8 beta(-) i- IEL from beta 2m(-/-) mice were expanded and functionally activated as a consequence of TcR gamma/delta engagement. The TcR gamma/delta i-IE L and TcR alpha/beta CD8 alpha/alpha(+) i-IEL from athymic nu/nu mice which express MHC class I, but lack TcR alpha/beta CD8/alpha/beta(+) i -IEL, responded to TcR gamma/delta engagement as those from the beta 2 (+/-) controls. In addition, the TcR/gamma/delta i-IEL from TcR beta(- /-) and TcRB beta(+/-) mutants were equally affected by GL3. We conclu de that the absence of beta 2m renders TcR gamma/delta i-IEL resistant to TcR-mediated inactivation and promotes activation of TcR alpha/bet a CD8 beta(-) i-IEL. The activation of TcR gamma/delta i-IEL seems to be directly controlled by beta 2m/MHC class I expression and independe nt from TcR alpha/beta CD8 beta(+) i-IEL. Regulation of self-reactive thymus-independent i-IEL through beta 2m/MHC class I may contribute to control of autoreactive immune responses in the intestine.