CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch.
The mechanisms whereby CD4 T cells contribute to the protective response against lethal influenza infection remain poorly characterized. To define the role of CD4 cells in protection against a highly pathogenic strain of influenza, virus-specific TCR transgenic CD4 effectors were generated in vitro and transferred into mice given lethal influenza infection. Primed CD4 effectors conferred protection against lethal infection over a broad range of viral dose. The protection mediated by CD4 effectors did not require IFN-gamma or host T cells, but did result in increased anti-influenza Ab titers compared with untreated controls. Further studies indicated that CD4-mediated protection at high doses of influenza required B cells, and that passive transfer of anti-influenza immune serum was therapeutic in B cell-deficient mice, but only when CD4 effectors were present. Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer protection. Pfn-deficient CD4 effectors were less able to promote survival in intact BALB/c mice and were unable to provide protection in B cell-deficient mice, indicating that Ab-independent protection by CD4 effectors requires Pfn. Therefore, CD4 effectors mediate protection to lethal influenza through at least two mechanisms: Pfn-mediated cytotoxicity early in the response promoted survival independently of Ab production, whereas CD4-driven B cell responses resulted in high titer Abs that neutralized remaining virus.
Brown
Deborah M
DM
Trudeau Institute, Saranac Lake, NY 12983, USA. dbrown@trudeauinstitute
Dilzer
Allison M
AM
Meents
Dana L
DL
Swain
Susan L
SL
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006389:Hemagglutinins, Viral / Q000276:immunology; D008168:Lung / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015996:Survival Rate; D017186:Titrimetry
D000914:Antibodies, Viral; D006389:Hemagglutinins, Viral; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin