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/beta+ 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. Whilst the development of the CD8 alpha/beta expressing i-IEL is strictly contingent on major histocompatibility complex (MHC) class I surface expression, that of CD8 alpha/alpha i-IEL appears largely MHC class I independent. We have used beta 2-microglobulin (beta 2m)-/- mutant mice lacking surface-expressed MHC class I and TcR alpha/beta CD8 alpha/beta+ i-IEL to analyze the potential impact of MHC class I on regional activation of thymus-independent i-IEL. To analyze the role of TcR gamma/delta i-IEL in regional cell interactions, these mice were treated 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 in vivo caused TcR down-modulation and functional inactivation of TcR gamma/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-IEL 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 2m+/- controls. In addition, the TcR gamma/delta i-IEL from TcR beta-/- and TCR beta+/- mutants were equally affected by GL3. We conclude that the absence of beta 2m renders TcR gamma/delta i-IEL resistant to TcR-mediated inactivation and promotes activation of TcR alpha/beta 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 independent 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.
Neuhaus
O
O
Department of Immunology, University of Ulm, Germany.
Emoto
M
M
Blum
C
C
Yamamoto
S
S
Kaufmann
S H
SH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping / Q000379:methods; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D001613:beta 2-Microglobulin