Human antigen presenting cells stimulate HBV specific CTL and Th cells in the trimera mouse model

Introduction: The strength and breadth of antiviral T cell response is correlated with disease outcome from hepatitis B. Thus, induction of HBV-specific T cells by therapeutic vaccination might represent a new therapeutic strategy, as demonstrated in the humanized trimera mouse model. However, nod.scid mouse derived antigen presenting cells (APC) might reconstitute together with transferred human B cells, monocytes and dendritic cells. Thus, it was hypothesized that murine APC might crosspresent vaccine derived epitopes to human T cells. Methods: To study this issue, Balb/c mice were lethally irradiated, reconstituted with nod.scid mouse bone marrow and transplanted with human PBMC from volunteers or chronic HBV carriers. Human PBMC were transferred either unmanipulated or depleted for total HLA DR⁺ APC, CD14⁺ monocytes, CD19⁺ B cells or BDCA–1⁺/–4⁺ DC. Vaccination of such trimera was performed i.p. with the Th cell antigens tetanus toxoid and recombinant HBV core (HBc) antigen, or with the synthetic CTL epitopes HBc_18–27 and EBV_280–288. Mouse APC were assessed by FACS analysis. Antigen specific human Th cell and CTL frequencies were analysed by IFNg ELISpot. Human cytokines were studied by cytokine bead array. Results: Very low but increasing numbers of mouse B cells and monocytes were detected in peritoenum, spleen and bone marrow of trimera mice. The only human cytokines detectable in peritoneal lavage were IL–1b, IL–6, IL–8 and IFNg. Very strong HBc and EBV specific Th cell and CTL responses were induced in vaccinated trimera mice implanted with total PBMC. Depletion of total DR⁺ APC, or BDCA–1⁺/–4⁺ DC led to abrogation of Th cell and CTL responses, demonstrating the need of human DC for T cell stimulation in trimera mice. In contrast, monocyte and B cell depletion only partly reduced HBc and EBV specific T cell responses. Conclusions: All three human APC populations contribute to effective stimulation of HBV specific human T cell responses in trimera mice, although only DC are indispensable. Mouse derived APC seem not to play a functionally relevant role in this mouse model. Thus, effective vaccination approaches in trimera mice should be predictive of similar responses in patients.

CTL induction - antigen presenting cells - chronic HBV infection - trimera mouse