title: Dysregulation of T lymphocyte proliferative responses in autoimmunity.
abstract: T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains-NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University, School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Sydney K
authors.initials: SK
authors.lastname: Elizer
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University, School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Marshall
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University, School of Medicine, Nashville, Tennessee, United States of America; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD