Serpinb9 (Spi6)-deficient mice are impaired in dendritic cell-mediated antigen cross-presentation.
Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (GrB) that protects activated cytotoxic lymphocytes from apoptosis. We show here that the CD8(+) subset of splenic dendritic cells (DC), specialized in major histocompatibility complex class I (MHC I) presentation of exogenous antigens (cross-presentation), produce high levels of Sb9. Mice deficient in Sb9 are unable to generate a cytotoxic T-cell response against cell-associated antigen by cross-presentation, but maintain normal MHC-II presentation to helper T cells. This impaired cross-priming ability is autonomous to DC and is evident in animals deficient in both Sb9 and GrB, indicating that this role of Sb9 in DC is GrB-independent. In Sb9-deficient mice, CD8(+) DC develop normally, survive as well as wild-type DC after antigenic challenge, and exhibit unimpaired capacity to take up antigen. Although the core processing machinery is unaffected, Sb9-deficient DC appear to process antigen faster. Our results point to a novel, GrB-independent role for Sb9 in DC cross-priming.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Alexandra
A
Rizzitelli
Simone
S
Meuter
Javier
J
Vega Ramos
Catherina H
CH
Bird
Justine D
JD
Mintern
Matthew S J
MS
Mangan
Jose
J
Villadangos
Phillip I
PI
Bird
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D006183:H-2 Antigens; D008565:Membrane Proteins; D015843:Serpins; D053804:Granzymes; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse