title: Granzyme B regulates antiviral CD8+ T cell responses.
abstract: CTLs and NK cells use the perforin/granzyme cytotoxic pathway to kill virally infected cells and tumors. Human regulatory T cells also express functional granzymes and perforin and can induce autologous target cell death in vitro. Perforin-deficient mice die of excessive immune responses after viral challenges, implicating a potential role for this pathway in immune regulation. To further investigate the role of granzyme B in immune regulation in response to viral infections, we characterized the immune response in wild-type, granzyme B-deficient, and perforin-deficient mice infected with Sendai virus. Interestingly, granzyme B-deficient mice, and to a lesser extent perforin-deficient mice, exhibited a significant increase in the number of Ag-specific CD8(+) T cells in the lungs and draining lymph nodes of virally infected animals. This increase was not the result of failure in viral clearance because viral titers in granzyme B-deficient mice were similar to wild-type mice and significantly less than perforin-deficient mice. Regulatory T cells from WT mice expressed high levels of granzyme B in response to infection, and depletion of regulatory T cells from these mice resulted in an increase in the number of Ag-specific CD8(+) T cells, similar to that observed in granzyme B-deficient mice. Furthermore, granzyme B-deficient regulatory T cells displayed defective suppression of CD8(+) T cell proliferation in vitro. Taken together, these results suggest a role for granzyme B in the regulatory T cell compartment in immune regulation to viral infections.
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Salti
authors.forename: Erin M
authors.initials: EM
authors.lastname: Hammelev
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Grewal
authors.forename: Sreelatha T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Zemple
authors.forename: William J
authors.initials: WJ
authors.lastname: Grossman
authors.forename: Mitchell H
authors.initials: MH
authors.lastname: Grayson
authors.forename: James W
authors.initials: JW
authors.lastname: Verbsky
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin / Q000172:deficiency / Q000235:genetics; D010253:Respirovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D029082:Sendai virus / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000821:virology; D019562:Viral Load / Q000235:genetics / Q000276:immunology*; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse
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