A Brucella spp. protease inhibitor limits antigen lysosomal proteolysis, increases cross-presentation and CD8+ T cell responses

LM. CORIA, AE. IBAÑEZ* M TKACH, F SABBIONE, L BRUNO, MV. CARABAJAL, P BERGUER, P BARRIONUEVO, R SCHILLACI, A TREVANI, GH GIAMBARTOLOMEI, KA. PASQUEVICH, J CASSATARO

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2016

0022-1767

In this study, wedemonstrate for the first time that the outer membrane protein U-Omp19 from Brucella spp. is a competitive inhibitor of human cathepsin L. U-Omp19 inhibitslysosome cathepsins in vivoand antigenpresenting cell derived microsomes activity invitro. Co-delivery ofU-Omp19 with the antigen (Ag) can reduce intracellular Ag digestion andincreases Ag half-life in dendritic cells (DC). U-Omp19retains the Ag in Lamp-2 positive compartments after its internalization andpromotes a sustained expression of MHCI-peptidescomplexes in the cell surface of DCs. Consequently, U-Omp19 enhances Agcross-presentation by DCs to CD8+ T cells. U-Omp19 s.c. deliveryinduces the recruitment of CD11c+ CD8α+ DCs and monocytesto lymph nodes while it partially limits in vivo Agproteolysis inside DCs. Accordingly, this protein is able to induce CD8+T cell responses in vivo againstco-delivered Ag. Anti-tumor responses were elicited after U-Omp19 co-administrationincreasing mice survival in a murine melanoma challenge model. Altogether,these results indicate that a cysteine protease inhibitor from bacterial origincould be a suitable component of vaccine formulations against tumors