Virus-induced activation of self-specific TCR alpha beta CD8 alpha alpha intraepithelial lymphocytes does not abolish their self-tolerance in the intestine.
TCRalphabeta CD8alphaalpha intestinal intraepithelial lymphocytes (IEL) represent an enigmatic subset of T cells, particularly, in regard to their potential functions and the apparent persistence of cells expressing self-specific TCR. We have used mice that are transgenic for the TCRalphabeta specific for the lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCRalphabeta-transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the functional properties of TCRalphabeta CD8alphaalpha IEL in the presence, or absence, of their specific MHC-restricted Ag, and to assess the impact of molecular mimicry during a potent LCMV infection on potentially self-reactive TCRalphabeta CD8alphaalpha IEL. In this study, we show that the presence of the specific self-Ag results in reduced expression of IL-2, IFN-gamma, and IL-10 by resident TCRalphabeta CD8alphaalpha IEL while expression of mRNA for TGFbeta is not affected. We further demonstrate that despite their secluded location in the epithelium, TCRalphabeta CD8alphaalpha IEL are activated after infection of the intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self-specific TCRalphabeta CD8alphaalpha IEL does not reverse their tolerance as no cytotoxic activity or up-regulated expression of proinflammatory cytokines is detected and no overt signs of autoimmunity are seen. Taken together, these results are in support of an immunoregulatory role for self-specific TCRalphabeta CD8alphaalpha in the intestinal mucosa and clearly speak against an involvement of this cell subset in inflammatory reactions and tissue destruction.
Saurer
Leslie
L
Institute of Pathology, Division of Immunopathology, University of Bern, Bern, Switzerland.
Seibold
Inge
I
Rihs
Silvia
S
Vallan
Claudio
C
Dumrese
Tilman
T
Mueller
Christoph
C
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D017634:Self Tolerance / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014764:Viral Proteins / Q000276:immunology
D000956:Antigens, Viral; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus