Sunday, May 11, 2025
5/11/2025
Understanding the Mechanisms of DC Licensing in CD8 T Cell Priming - ABSTRACT Effective responses to viruses, intracellular pathogens and tumors rely on the successful expansion and arming of cytolytic CD8 T cells from a naïve and quiescent T cell repertoire. This process, called CD8 T cell priming, is dependent on a specialized antigen-presenting cell known as conventional dendritic cells (cDCs). Recent studies from our lab have shown that a specific type of dendritic cells, called cDC1, is responsible for CD8 T cell priming and depends on the transcription factor Batf3 for development. In the process of priming CD8 T cells, the cDC1 captures foreign antigens or tumor-specific neo-antigens, and presents these antigens on the MHC-I molecule in order to stimulate the T cell receptor (TCR) of the CD8 T cell. In the absence of cDC1, such as in Batf3-deficient mice, CD8 T cells are not activated against viruses or tumors. In addition, however, full activation of CD8 T cell requires that cDC1 receive signals that program its ability to fully activate CD8 T cells. This process is called `DC licensing', but is currently not fully characterized. Our recent work has shown that current models for DC licensing are incomplete. Specifically, while we have confirmed the requirement for CD40 signaling in response to CD40L provided by a helper cell, we have shown that the expected target of CD40, CD70, does not explain the beneficial effect of DC licensing for tumor rejection. This result implies that additional targets of CD40 are needed to understand DC licensing. Further, it has been thought that CD4 T cells are the exclusive agent in the licensing process. However, these conclusions derived from older studies and less precise methods. In contrast, we developed an Xcr1-Cre deletor strain to delete genes specifically from cDC1, and found unexpected results, that CD4 T cells are not always critical for cDC1 licensing, suggesting that other cells expressing CD40L may be involved. Further, mechanism by which CD40 signaling induces licensing of the cDC1 is unclear. Several mechanisms have been proposed, but our preliminary data excludes the major proposed mechanism, those invoking CD70, as being critical for the effect of licensed cDC1 in priming CD8 T cells. Our proposal will first test (Aim 1) which Batf3-specific genes expressed in cDC1 are important for cDC1 to support CD8 T cells responses. Second (Aim 2), we will determine identify the targets of CD40 signaling in cDC1 that are required for fully activating CD8 T cells. Finally, in Aim 3, we will test the role of cells that we have identified as alternative sources of CD40 ligand, including iNKT cells and γδ T cells.
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