IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4 + T cells

CD4 T cell effectors can promote survival against lethal influenza virus via perforin mediated cytolytic mechanisms; however, our understanding of how naïve CD4 cells differentiate into class II restricted killers remains obscure. To address this, TCR Tg CD4 cells were activated in vitro and examine...

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Bibliographic Details
Published in:Cellular immunology 2009, Vol.257 (1), p.69-79
Main Authors: Brown, Deborah M., Kamperschroer, Cris, Dilzer, Allison M., Roberts, Deborah M., Swain, Susan L.
Format: Article
Language:English
Subjects:
Animals
Antigens - immunology
CD4 subsets
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
Cell Differentiation - drug effects
Cell Differentiation - immunology
Cytokines - immunology
Cytokines - metabolism
Cytotoxicity
Cytotoxicity, Immunologic
Dendritic Cells - immunology
Dendritic Cells - metabolism
Fas Ligand Protein - immunology
Fas Ligand Protein - metabolism
Granzymes - immunology
Granzymes - metabolism
Hemagglutinins, Viral - immunology
IL-2
Interferon-gamma - immunology
Interferon-gamma - metabolism
Interleukin-2 - immunology
Interleukin-2 - pharmacology
Interleukin-4 - immunology
Interleukin-4 - metabolism
Interleukin-4 - pharmacology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Ovalbumin - immunology
Peptide dose
Peptide Fragments - immunology
Perforin
Perforin - genetics
Perforin - immunology
Perforin - metabolism
T-Lymphocytes, Cytotoxic - drug effects
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Th1 Cells - immunology
Th1 Cells - metabolism
Th2 Cells - immunology
Th2 Cells - metabolism
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Summary:CD4 T cell effectors can promote survival against lethal influenza virus via perforin mediated cytolytic mechanisms; however, our understanding of how naïve CD4 cells differentiate into class II restricted killers remains obscure. To address this, TCR Tg CD4 cells were activated in vitro and examined for their ability to lyse target cells. We found that cytokine polarized CD4 T cell effectors displayed cytolytic activity with the hierarchy Th0 > Th1 > Th2. Further, IL-4 inhibited the generation of cytotoxic CD4 cells. LPS stimulated B cells and bone marrow derived dendritic cells (BMDC) both induced potent cytolytic activity; however, IL-6, TGF-β, IL-10, IL-12 or TNF-α were not required for inducing cytolytic activity in CD4 effectors. Antigen dose had a marked effect on cytotoxicity: low concentrations of peptide induced more potent cytolytic activity than relatively high concentrations. At low peptide concentration, exogenous IL-2 was necessary to drive granzyme B (GrB) expression and perforin mediated lysis. Thus, low antigen dose and early activation signals via IL-2 direct the CD4 T cell response toward effectors with perforin mediated cytolytic potential. These data have implications for the design of vaccines that may induce cytolytic CD4 cells in vivo and improve cell-mediated immunity to viral and bacterial infections.
ISSN:0008-8749
1090-2163
DOI:10.1016/j.cellimm.2009.03.002