Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

Abstract

To develop cytolytic effector functions, CD8 1 T lymphocytes need to recognize specific Ag/ MHC class I complexes in the context of costimuli on Ag-presenting DC. Thereafter they differentiate into effector and memory CTL able to confer protection against pathogen infection. Using transgenic mice with DC-selective MHC class I expression and DC-specific versus ubiquitous vaccination regimen, we found that DC are sufficient to prime CTL responses. However, Ag recognition on parenchymal non-professional APC negatively affected CD8 1 T-cell responses in mice by inducing expression of the pro-apoptotic bcl2-family member bim in CTL. This unexpected induction of apoptosis in the early phase of effector CTL accumulation lead to suboptimal clonal burst size and diminished long-term memory. Thus, our data demonstrate that effector CTL differentiation and apoptosis are regulated independently. Moreover, Ag distribution on cells other than DC critically reduces CTL responses.

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

“…Mice AND (Tg(TcrAND)53Hed) (37), OT-1 (Tg(TcraTcrb)1100Mjb) (38), invariant chain-moth cytochrome c (Ii-MCC) (Tg(H2-Ea-Cd74/MCC)37GNnak) (39), Ii-reverse transactivator (rTA) (Tg(Cd74-rtTA)#Doi), tet-inducible modified Ii MCC (Tg(tetO-Cd74/MCC)#Doi) (28), CD11c-b 2 m and K14-b 2 m transgenics, and B2m tm1Jae (40), and Cd274 tmiLpc mice (41) have been described previously. Animals were kept on the C57BL/6 (B6) and the B10.BR/SgSnJ (The Jackson Laboratory) backgrounds.…”

“…Therefore, we used recipients that were deleted of their b 2 m genes and hence lack MHC class I surface expression but were replete with a transgene expressed in thymic cortical epithelium to allow for the selection of a full T cell compartment, thus reining in lymphopenia-driven proliferation of adoptively transferred CD8 + T cells. Recipients carrying an additional DC-targeted b 2 m transgene served as positive controls (40). However, when 2-dstimulated CD8 + T cells were transferred into such Ag-free hosts, they proliferated, regardless of MHC class I expression on peripheral cells (Fig.…”

CD169+macrophages are sufficient for priming of CTLs with specificities left out by cross-priming dendritic cells

“…To determine whether the two APC types prime CTLs of different specificities, we used mice in which only DCs and thymic epithelial cells, and no other cell types, express MHCI molecules (26). These animals generate a normal CD8 + T-cell repertoire that can be primed only by MHCI + DCs (27). Using this model, we previously showed that DCs are sufficient to prime different virus-specific CTL responses (27)(28)(29) and to cross-present the model Ag OVA to OTI T cells (26).…”

“…These animals generate a normal CD8 + T-cell repertoire that can be primed only by MHCI + DCs (27). Using this model, we previously showed that DCs are sufficient to prime different virus-specific CTL responses (27)(28)(29) and to cross-present the model Ag OVA to OTI T cells (26). Surprisingly, DC-MHCI mice injected with rAd-GP mounted nearly exclusively K b /GP33-specific CTL responses, with strongly reduced D b /GP33-specific responses and undetectable D b /GP276-specific responses (Fig.…”