Influence of β2-microglobulin expression on gamma interferon secretion and target cell lysis by intraepithelial lymphocytes during intestinal Listeria monocytogenes infection

Abstract

Numerous microbial pathogens, including Listeria monocytogenes, enter the host through the intestine. Although relatively little is known about the biological functions of intestinal intraepithelial lymphocytes (i-IEL), they are generally considered a first line of defense against intestinal infections. In the mouse, the vast majority of i-IEL express the CD8 coreceptor either as a CD8α/α homodimer or as a CD8α/β heterodimer. The CD8 coreceptor of T-cell receptor (TcR)γ/δ i-IEL is exclusively homodimeric, whereas the CD8-expressing TcRα/β i-IEL segregate into equal fractions of CD8α/α and CD8α/β cells. We infected β2-microglobulin (β2m)(+/-) mice (possessing all i-IEL populations) and β2m(-/-) mutant mice (lacking all CD8α/β+ i-IEL and having few CD8α/α+ TcRα/β i-IEL) with L. monocytogenes per os and determined their biological functions after TcR ligation with monoclonal antibodies. Cytolytic activities of TcRα/β and TcRγ/δ i-IEL from β2m(+/-) mice were not influenced by intestinal listeriosis. Cytolytic activities of TcRα/β i-IEL were impaired in uninfected β2m(-/-) mice, but this reduction was reestablished as a consequence of intestinal listeriosis. Frequencies of gamma interferon (IFN- γ)-producing TcRα/β i-IEL in uninfected β2m(-/-) mice were reduced, compared with that in their heterozygous controls. Equally low frequencies of IFN-γ-producing TcRγ/δ i-IEL in β2m(+/-) and β2m(-/-) mutants were found. Listeriosis increased frequencies of IFN-γ-producing TcRα/β and TcRγ/δ i-IEL in both mouse strains. Most remarkably, the proportion of IFN- γ-producing TcRγ/δ i-IEL was elevated 10-fold in listeria-infected β2m(- /-) mice. Our findings show that the β2m-independent CD8β- i-IEL expressing either TcRα/β or TcRγ/δ are stimulated by intestinal listeriosis independent of regional β2m expression. We conclude that the three major CD8+ i-IEL populations are stimulated by intestinal listeriosis and that CD8β- i-IEL compensate for the total lack of CD8β+ i-IEL in β2m(-/-) mutant mice. Hence, in contrast to the peripheral immune system, which crucially depends on CD8α/β+ TcRα/β lymphocytes, the mucosal immune system can rely on additional lymphocytes expressing the CD8α/α homodimer.