CD40 signaling in CD8+CD40+ T cells turns on contra-T regulatory cell functions.
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.
Martin
Sunil
S
National Centre for Cell Science, Ganeshkhind, Pune, India.
Pahari
Sushmita
S
Sudan
Raki
R
Saha
Bhaskar
B
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000637:transplantation; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D053804:Granzymes / Q000096:biosynthesis / Q000633:toxicity; D007893:Leishmania donovani / Q000254:growth & development / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054353:Perforin / Q000096:biosynthesis / Q000633:toxicity; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology
D019013:CD40 Antigens; D054353:Perforin; D053804:Granzymes