Control of thymus‐independent intestinal intraepithelial lymphocytes by β2‐microglobulin

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Abstract
Murine intestinal intraepithelial lymphocytes (i-IEL) comprise thymusdependent cells such as T cell receptor (TcR) α/β CD8α/β+ i-IEL, as well as thymus-independent ones such as TcRα/β CD8α/α+ and TcRγ/δ CD8α/α+ i-IEL. Whilst the development of the CD8α/β expressing i-IEL is strictly contingent on major histocompatibility complex (MHC) class I surface expression, that of CD8α/α i-IEL appears largely MHC class I independent. We have used β2-microglobulin (β2m)−/− mutant mice lacking surface-expressed MHC class I and TcRα/β CD8α/β+ i-IEL to analyze the potential impact of MHC class I on regional activation of thymus-independent i-IEL. To analyze the role of TcRγ/δ i-IEL in regional cell interactions, these mice were treated with the anti-TcRγ/δ mAb, GL3. Whilst numbers of TcRα/β CD8α/α i-IEL were markedly reduced in βm+/− mice, those of TcRγ/δ i-IEL were elevated. Administration of GL3 in vivo caused TcR down-modulation and functional inactivation of TcRγ/δ i-IEL in β2m+/− mice. In contrast, TcR expression and functional activities of TcRγ/δ i-IEL from β2m−/− mice were not impaired by GL3 treatment. The TcRα/β CD8β i-IEL from β2m−/− mice were expanded and functionally activated as a consequence of TcRγ/δ engagement. The TcRγ/δ i-IEL and TcRα/β CD8α/α+ i-IEL from athymic nu/nu mice which express MHC class I, but lack TcRα/β CD8α/β+ i-IEL, responded to TcRγ/δ engagement as those from the β2m+/− controls. In addition, the TcRγ/δ i-IEL from TcRβ−/− and TcRβ+/− mutants were equally affected by GL3. We conclude that the absence of β2m renders TcRγ/δ i-IEL resistant to TcR-mediated inactivation and promotes activation of TcRα/β CD8β− i-IEL. The activation of TcRγ/δ i-IEL seems to be directly controlled by β2m/MHC class I expression and independent from TcRα/β CD8β+ i-IEL. Regulation of self-reactive thymus-independent i-IEL through β2m/MHC class I may contribute to control of autoreactive immune responses in the intestine.