Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice.
Cellular FLICE inhibitory protein--long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. c-FLIP(L) expression in T cells can also augment activation of the mitogen-activated protein kinase, extracellular signal-related kinase, as well as nuclear factor-kappaB. This contributes to increased production of interleukin-2 and CD25, resulting in hyperproliferation of T cells from c-FLIP(L)-transgenic mice. c-FLIP also heterodimerizes with and activates caspase-8, resulting in increased death of T cells and a selection of a T helper 2 cytokine profile. The effects of c-FLIP on cytolytic function of CD8(+) T cells have not been examined previously. We studied the cytolytic capacity of T cells from c-FLIP(L)-transgenic mice using an antigen-specific system, as well as the consequences during a viral immune response to Coxsackievirus B3 (CVB3). The increased T-cell receptor (TCR) signalling due to c-FLIP did not alter the cytolytic machinery but did reduce cytotoxicity because of decreased surface expression of TCR and CD8. It also produced a Tc2 cytokine profile. These effects of c-FLIP collectively served to diminish the severity of CVB3-induced myocarditis.
Huber
Sally
S
Department of Pathology, The University of Vermont College of Medcine, Burlington, VT, USA.
Dohrman
Austin
A
Sartini
Danielle
D
Budd
Ralph C
RC
D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology*; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D029822:Enterovirus B, Human; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell