Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity.
To determine the role of perforin-mediated cytotoxic T lymphocyte (CTL) effector function in immune regulation, we studied a well-characterized mouse model of graft-versus-host disease (GVHD). Induction of acute GVHD using perforin-deficient donor T cells (pfp-->F1) initially resulted in features of acute GVHD, e.g., engraftment of both donor CD4(+) and CD8(+) T cells, upregulation of Fas and FasL, production of antihost CTL, and secretion of both Th1 and Th2 cytokines. Despite fully functional FasL activity, pfp donor cells failed to totally eliminate host B cells, and, by 4 weeks of disease, cytokine production in pfp-->F1 mice had polarized to a Th2 response. Pfp-->F1 mice eventually developed features of chronic GVHD, such as increased numbers of B cells, persistence of donor CD4 T cells, autoantibody production, and lupuslike renal disease. We conclude that in the setting of B- and T-cell activation, perforin plays an important immunoregulatory role in the prevention of humoral autoimmunity through the elimination of both autoreactive B cells and ag-specific T cells. Moreover, an ineffective initial CTL response can evolve into a persistent antibody-mediated response and, with it, the potential for sustained humoral autoimmunity.
Shustov
A
A
Research Service, Department of Veteran Affairs Medical Center, Baltimore, Maryland, USA.
Luzina
I
I
Nguyen
P
P
Papadimitriou
J C
JC
Handwerger
B
B
Elkon
K B
KB
Via
C S
CS
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000276:immunology; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
D001323:Autoantibodies; D016207:Cytokines; D004277:DNA, Single-Stranded; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007132:Immunoglobulin Isotypes; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin