Abstract
CD4(+) regulatory T cells (Treg cells) mediate immunosuppression, whereas CD8(+) T cells confer resistance in many diseases. It is unknown whether CD8(+) T cells confer protection by antagonizing the Treg cells. Using a model of stage-specific immune responses against Leishmania donovani infection in susceptible BALB/c mice, we report that CD3(+)CD8(+)CD40(+) T cells executed CD40-dependent cytotoxicity on CD3(+)CD4(+)CD127(dim)GITR(+)CD25(+) Treg cells during the initial phase of the infection but were later apoptosed by IL-10. CD40 signaled through Ras, PI3K, and protein kinase C, resulting in p38MAPK- or ERK-1/2-independent, but NF-kappaB-dependent, induction of the cytotoxic mediators granzyme and perforin. Adoptive transfer of CD3(+)CD8(+)CD40(+) T cells reduced the L. donovani infection in BALB/c mice. These results identify CD3(+)CD8(+)CD40(+) T cells as the contra-Treg cells and imply a novel immunotherapeutic principle.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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CD40 Antigens / biosynthesis
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CD40 Antigens / deficiency
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CD40 Antigens / genetics
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CD40 Antigens / physiology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / parasitology
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / transplantation
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Cell Communication / genetics
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Cell Communication / immunology
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Cytotoxicity, Immunologic* / genetics
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Disease Models, Animal
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Genetic Predisposition to Disease
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Granzymes / biosynthesis
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Granzymes / toxicity
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Leishmania donovani / growth & development
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Leishmania donovani / immunology
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Leishmaniasis, Visceral / immunology*
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Leishmaniasis, Visceral / pathology
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Leishmaniasis, Visceral / therapy
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Perforin / biosynthesis
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Perforin / toxicity
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Severity of Illness Index
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / parasitology
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T-Lymphocytes, Cytotoxic / transplantation
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / parasitology
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T-Lymphocytes, Regulatory / pathology
Substances
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CD40 Antigens
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Perforin
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Granzymes