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We and multiple collaborators have begun to analyze the role of autophagy-related genes in mice infected with Toxoplasma gondii, Mycobacterium tuberculosis (M.tb.), influenza,lymphocytic choriomeningitis virus (LCMV) or murine gammaherpesvirus 68 (MHV68).Mice lacking Atg5, Atg3, Atg7, Atg5, or Atg 16L1 in macrophages and neutrophils (through Lysozyme-M-cre-mediated deletion) were highly susceptible to infection with T.gondii due to a key role of Atg proteins in interferon-gamma-induced killing of intracellular parasites.In contrast, Atg14,ULK-1, ULK-2and the degradative function of autophagy were not involved (Choi et al.2014 Immunity 40∶924).Deletion of Epg-5in the whole animal or of Atg5, Atg7, FIP200 or Atg14 in macrophages and neutrophils, created a striking hyper-inflammatory state in the lung of even uninfected mice.One consequence of this was striking resistance to influenza infection.In contrast, systemic inflammation characterized by increased neutrophils and serum interferon-gamma developed in MHV68-infected mice lacking Atg5, Atg7, Atg14, or Atg16L1 in macrophages and neutrophils.One consequence of this was diminished herpesvirus reactivation from latency.As expected, mice lacking Atg5in macrophages and neutrophils were highly susceptible to lethal infection with M.tb.Work in the lab of our collaborator Christina Stallings found that this phenotype was characterized by neutrophilic hyper-inflammation.Importantly, lack of other Atg genes in these same cells did not result in this phenotype, and depletion of neutrophils restored normal resistance of Atg5-deficient mice to infection with M.tb.Thus the key role of Atg5in vivo during M.tb.infection is through regulation of neutrophilic inflammation.Analysis of the role of Atg genes in T cells (using Granzyrne-B-cre-mediated deletion) revealed a striking repression of autophagy in proliferating CD8 T cells followed by induction of autophagy during the contraction phase of the T cell response.Loss of Atg5 or Atg7 resulted in diminution of memory responses during virus infection (Xu et al.Nature Immunology 2014 15.∶1152).Together, these studies reveal that the autophagy pathway and individual Atg genes have fundamentally important Atg-gene-specific, tissue-specific and pathogen-specific roles in innate and adaptive immunity and the regulation of inflammation.