The role of T cell-associated polarizing transcription factors in dendritic cell priming of T cells towards immunity or tolerance; role of T-bet or Foxp3 ectopic expression in dendritic cells

Dendritic cells (DC) are professional antigen presenting cells that can prime naive T cells to elicit immunity or tolerance. The ability to regulate immunity or tolerance is governed by the "type" of polarization state of activated T cells. T-bet has been identified as the master regulator of Type 1 polarization in T cells, and its expression is essential for immunity. Interestingly, T-bet is also expressed in DC and its abolishment has been shown to impair Type-1 T cell responses in limited studies. Conversely, Foxp3 expression in T regulatory cells engenders a tolerogenic phenotype that can suppress T cell responses (as well as DC induction of immunity). Foxp3 expression in non-T cell subsets, such as adenocarinoma, has also shown immunosuppressive characteristics in the tumor microenvironment and draining lymph nodes. Therefore, I examined the role of T-bet or Foxp3 expression in the DC in modulating T cell responses. T cells were primed with T-bet expressing DC (DC.T-bet) or Foxp3 expressing DC (DC.Foxp3) and responses were thoroughly investigated. DC.T-bet potently primed naive T cells towards Type 1 immunity, inducing 2-3 fold increased levels of T-bet, IFNgamma, CXCR3, and Granzyme-B. Little-to-no changes were found in DC costimulatory molecule expression, however, DC were completely impaired in production of pro-inflammatory and Type-1-inducing cytokines. We confirmed cytokine-independent Type 1 polarization of T cells via neutralization studies. In analogous studies, Foxp3 ectopic expression in DC was found to restrain Type 1 and 17 polarized T cell responses while concomitantly generate CD4+Foxp3+CD25+ T regulatory cell subsets that co-expressed high levels of CTLA-4, CD25, NRP-1 and GITR. These in vitro generated T regulatory cells (by DC.Foxp3 and not control DC) suppressed both naive and memory CD8+ T cell proliferation and IFNgamma production. Neutralizing agents confirmed that the tryptophan catabolizing enzyme-IDO and the immunosuppressive cytokine TGFbeta were partially dependent for both suppressing Type 1 T cell responses and generating functionally suppressive Tregs. In summation, this work shows that T-bet and Foxp3 expression in DC play similar roles to expression in T cells by governing immunity or tolerance, respectively.