Δ42PD1-TLR4 Augments γδ-T Cell Activation of the Transitional Memory Subset of CD4+ T Cells

TLR ligands can contribute to T cell immune responses by indirectly stimulating antigen presentation and cytokines and directly serving as co-stimulatory signals. We have previously reported that the human endogenous surface protein, Delta 42PD1, is expressed primarily on (V gamma 9)V delta 2 cells and can interact with TLR4. Since V delta 2 cells possess antigen presentation capacity, we sought to further characterize if the Delta 42PD1-TLR4 interaction has a role in stimulating T cell responses. In this study, we found that stimulation of V delta 2 cells not only upregulated Delta 42PD1 expression but also increased MHC class II molecules necessary for the antigen presentation. In a mixed leukocyte reaction assay, upregulation of Delta 42PD1 on V delta 2 cells elevated subsequent T cell proliferation. Furthermore, the interaction between Delta 42PD1-TLR4 augments V delta 2 cell stimulation of autologous CMV pp65-or TT-specific CD4(+) T cell proliferation and IFN-gamma responses, which was specifically and significantly reduced by blocking the Delta 42PD1-TLR4 interaction. Furthermore, confocal microscopy analysis confirmed the interaction between Delta 42PD1(+)HLA-DR+V delta 2 cells and TLR4(+)CD4 T cells. Interestingly, the subset of CD4(+) T cells expressing TLR4 appears to be PD-1(+) CD45RO(+)CD45RA(+) transitional memory T cells and responded to Delta 42PD1(+)HLA-DR+V delta 2 cells. Overall, this study demonstrated an important biological role of Delta 42PD1 protein exhibited by V delta 2 antigen-presenting cells in augmenting T cell activation through TLR4, which may serve as an additional co-stimulatory signal.