Hypo-active variant of IL-2 and associated decreased T cell activation contribute to impaired apoptosis in autoimmune prone MRL mice.
Apoptosis of activated lymphocytes is crucial to the maintenance of immune homeostasis and self-tolerance, as demonstrated by the well-known autoimmune MRL lpr mouse lacking the death receptor Fas. However, even MRL+/+ activated T cells have a resistance to Fas-mediated apoptosis as compared to T cells from the non-autoimmune FVB/N strain. To understand the molecular mechanisms underlying these strain differences, we studied biochemical characteristics of T cells upon activation. Compared to FVB/N T cells, MRL T cells under-expressed procaspase-3 but over-expressed FLIP(L). In addition, up-regulation of Bcl-x(L), IL-2, and CD25 was diminished in MRL cells, suggesting inadequate T cell activation. Upon finding that MRL, like other autoimmune strains NOD and SJL, has a hypo-active variant of the IL-2 gene, we added wild-type murine recombinant (mr)IL-2 during activation. Exogenous mrIL-2 restored MRL apoptosis to the level of FVB/N; in addition, expression of procaspase-3, and FLIP(L), Bcl-x(L) and CD25 was normalized. These results suggest that defective MRL T cell activation, in part due to hypo-active IL-2, underlies the impaired apoptosis of this strain. In addition, the hypo-active variant of IL-2 shared among autoimmune strains may, by causing diminished cell activation and cell death, predispose these strains to develop autoimmune disease.
Choi
Youngnim
Y
College of Dentistry and Research Institute of Oral Science, Kangnung National University, Kangnung, Korea. youngnim@kangnung.ac.kr
Simon-Stoos
Karen
K
Puck
Jennifer M
JM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D003208:Concanavalin A / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D007376:Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D023421:Models, Animal; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology
C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D004792:Enzyme Precursors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D019014:fas Receptor; D003208:Concanavalin A; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases