A role for perforin in downregulating T-cell responses during chronic viral infection.
Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf -/-) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf -/- mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral "exhaustion" of activated CD8 T cells occurred less efficiently in perf -/- mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf -/- mice; approximately 50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.
Matloubian
M
M
Department of Microbiology and Immunology, University of California, Los Angeles, California 90024, USA.
Suresh
M
M
Glass
A
A
Galvan
M
M
Chow
K
K
Whitmire
J K
JK
Walsh
C M
CM
Clark
W R
WR
Ahmed
R
R
D000818:Animals; D017252:CD3 Complex / Q000502:physiology; D002908:Chronic Disease; D015536:Down-Regulation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology