ABSTRACT One crucial barrier mechanism via which the skin defends against microbial infection involves the innate immune function of the epidermis. This function is partly mediated by Langerhans cells (LCs), which are a skin- specific resident dendritic cell (DC) subset. We found that LCs contribute to the cutaneous immune response to Mycobacterium leprae (mLEP, the causative agent of leprosy) via a CD1a-restricted antigen presentation pathway to T cells, which reflects correlations with the self-limiting vs. the progressive clinical forms of leprosy . CD1a+ LC also increase during reversal reactions (RR), when patients upgrade from the lepromatous to the tuberculoid pole. Our findings during the past 4 years of funding reveal new paradigms: 1) autophagy links antigen presentation to antimicrobial activity in LCs; 2) LC-intrinsic antibacterial mechanisms and mechanisms by which CD1a-restricted T cells kill bacteria in LCs; and 3) novel evidence that CD1a-restricted T cells recognize microbial peptides. Based on these findings, we hypothesize that CD1a-restricted presentation of microbial peptide antigens induces T cell dependent antimicrobial pathways in infected LCs. We propose to use leprosy as a model to examine this new concept that CD1a-restricted T cell and LC immunobiology are linked in host defense in skin. We propose to: 1) determine intrinsic pathways by which activated LC kill intracellular bacteria, 2) investigate the mechanisms by which CD1a-restricted T cells kill mLEP in LC; and, 3) define mechanisms by which LC process and present CD1a-restricted bacterial peptides to T cells. These studies are intended to provide a comprehensive and in-depth view of CD1-restricted T cell function and LC biology in relation to a model of human skin disease, leprosy. The goal is to understand mechanisms of host defenses against microbial pathogens in skin.