Ippolito, G. C. | Search bioRxiv

bioRxiv2018

Lymphoid origin of a lineage of intrinsically activated plasmacytoid dendritic cell in mice and humans

We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a. These CLP-derived pDCs, which we refer to as "B-pDCs", have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN- secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid derived pDCs, display elevated levels of the cell-surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice.

immunology↗

bioRxiv2017

Identification of Tumor-Reactive B Cells and Systemic IgG in Breast Cancer Based on Clonal Frequency in the Sentinel Lymph Node

A better understanding of antitumor immune responses is key to advancing the field of cancer immunotherapy. Endogenous immunity in cancer patients, such as circulating anticancer antibodies or tumor-reactive B cells, has been historically yet incompletely described. Here, we demonstrate that tumor-draining (sentinel) lymph node (SN) is a rich source for tumor-reactive B cells that give rise to systemic IgG anticancer antibodies circulating in the bloodstream of breast cancer patients. Using a synergistic combination of high-throughput B-cell sequencing and quantitative immunoproteomics, we describe the prospective identification of tumor-reactive SN B cells (based on clonal frequency) and also demonstrate an unequivocal link between affinity-matured expanded B-cell clones in the SN and antitumor IgG in the blood. This technology could facilitate the discovery of antitumor antibody therapeutics and conceivably identify novel tumor antigens. Lastly, these findings highlight the unique and specialized niche the SN can fill in the advancement of cancer immunotherapy.\n\nSIGNIFICANCEUsing high-throughput molecular cloning and antibody proteomics to study coordinated antitumor immunity in breast cancer patients, we simultaneously demonstrate that the sentinel lymph node is a localized source of expanded antitumor B cells undergoing affinity maturation and that their secreted antibodies are abundant as systemic IgG circulating in blood.

immunology↗