The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8 T cells.

Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8 T cells. T cell-specific ablation of resulted in loss of naïve CD8 T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner.

Activation of CD8⁺ T Cell Responses after Melanoma Antigen Targeting to CD169⁺ Antigen Presenting Cells in Mice and Humans.

The lack of tumor-reactive T cells is one reason why immune checkpoint inhibitor therapies still fail in a significant proportion of melanoma patients. A vaccination that induces melanoma-specific T cells could potentially enhance the efficacy of immune checkpoint inhibitors. Here, we describe a vaccination strategy in which melanoma antigens are targeted to mouse and human CD169 and thereby induce strong melanoma antigen-specific T cell responses.

Comparison of Protein and Peptide Targeting for the Development of a CD169-Based Vaccination Strategy Against Melanoma.

CD169 macrophages are part of the innate immune system and capture pathogens that enter secondary lymphoid organs such as the spleen and the lymph nodes. Their strategic location in the marginal zone of the spleen and the subcapsular sinus in the lymph node enables them to capture antigens from the blood and the lymph respectively. Interestingly, these specific CD169 macrophages do not destroy the antigens they obtain, but instead, transfer it to B cells and dendritic cells (DCs) which facilitates the induction of strong adaptive immune responses.

Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8 T Cell Cross-Priming.

Splenic CD169 macrophages are located in the marginal zone to efficiently capture blood-borne pathogens. Here, we investigate the requirements for the induction of CD8 T cell responses by antigens (Ags) bound by CD169 macrophages. Upon Ag targeting to CD169 macrophages, we show that BATF3-dependent CD8α dendritic cells (DCs) are crucial for DNGR-1-mediated cross-priming of CD8 T cell responses.

Targeting C-type lectin receptors: a high-carbohydrate diet for dendritic cells to improve cancer vaccines.

There is a growing understanding of why certain patients do or do not respond to checkpoint inhibition therapy. This opens new opportunities to reconsider and redevelop vaccine strategies to prime an anticancer immune response. Combination of such vaccines with checkpoint inhibitors will both provide the fuel and release the brake for an efficient anticancer response.