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Understanding Macrophages and DC Functional Heterogeneity to Improve Rationale Immunotherapy Approaches:

       A central dogma in immunology posits that monocytes and macrophages are part of a continuum that forms the mononuclear phagocyte system (MPS). Challenging the well established MPS dogma, our laboratory discovered, using parabiotic mice and fate mapping models of embryonic precursors, that many tissue resident macrophages arise from embryonic precursors that take residence in tissues prior to birth and self renew locally independent of adult hematopoiesis (Nature Immunology 2002; Nature Immunology 2006; Nature Reviews Immunol 2008;  Science 2010; JEM 2012; Immunity 2013; Nature Reviews Immunol 2015). In response to inflammatory signals, however, monocytes accumulate in injured tissues and differentiate into monocyte-derived cells that may resemble tissue resident macrophages. These findings have important clinical implications, as we found that embryonic-derived macrophages (but not monocyte-derived cells) are resistant to genotoxic stress, and this contributes to graft-versus-host disease after allogeneic bone marrow transplantation in mice (Nature Medicine 2004) and human (JID 2011), and to tumor resistance to radiotherapy (Nature Immunology 2015). Thus, tissue resident macrophages and monocyte-derived cells that accumulate in injured tissues should not be treated as equal and, currently, one of the main goals of the laboratory is to examine the contribution of these distinct macrophage lineages to disease pathogenesis.

       Our laboratory has also made pioneering discoveries in dendritic cell (DC) biology, including mapping the regulatory network of DCs and identification of a lineage of DC, the CD103+ DC, which are specialized in the induction of CD8+ T-cell immunity (JEM 2009; Immunity 2009; JCI 2012; Annual Reviews Immunol 2013). The human counterpart of CD103+ DC are now considered a key target to improve antiviral and antitumor immunity. Currently, another main goal of the laboratory is to continue to explore the contribution of CD103+ DC to tumor immunity.