The incidence of tuberculosis is significantly higher among the Canadian First Nations populations compared to Caucasians. More than two decade ago it was Paclitaxel Microtubule inhibitor demonstrated that vitamin D could inhibit Mycobacterium tuberculosis growth, and recently an association was demonstrated between vitamin D insufficiency and patients with TB. Recent studies have demonstrated that vitamin D metabolites can promote innate immune responses required for the elimination of Mtb, largely by inducing the expression of human host defence peptide cathelicidin LL-37. Lower level of vitamin D has been linked to lower expression of LL-37 in monocytes, thus contributing to higher susceptibility to TB in African-Americans. Consistent with this, LL-37 has been demonstrated to be protective in various animal models of infections and sepsis. The biological function of LL-37 in controlling infections is suggested to be largely due to the immunomodulatory functions mediated by the peptide, which includes tissue repair, induction of innate immune responses, influencing the differentiation and polarization of dendritic cells and T-cells, and autophagy. The gene encoding for LL-37 is a direct target of the vitamin D/vitamin D receptor complex. Thus it may be hypothesized that vitamin D insufficiency may result in decreased expression of LL-37 and impaired immune responses to Mtb, contributing to increased susceptibility to TB. Function of the vitamin D-LL-37 axis in immune responses to Mtb has not been investigated among Canadian FN populations. A previous study showed that Canadian Dene´ and Cree FN have a higher frequency of single nucleotide polymorphisms associated with low expression of vitamin D receptor and interferon-c, potentially contributing to increased risk of TB disease. A recent study has also shown that cellular regulation of lymphocytes mediated by killer immunoglobulin-like receptors may be different in Canadian Oji-Cree FN compared to Caucasians, which in turn can contribute to differential outcome to infectious challenge. These findings suggest that although social and environmental risk factors for disease contribute greatly to the increased burden of morbidity and mortality associated with TB in Canadian FN populations, underlying immune responses if differentially regulated may also play a role. We are engaged in a participatory research partnership with the Dene´ FN community of Lac Brochet in northern Manitoba, Canada, in order to elucidate the biologic and social determinants of TB, a disease that remains endemic among their people. There is no legal definition for the term “First Nations”, but it may be understood to mean a band within the meaning of the Canadian Indian Act, which includes Dene, Cree, Ojibwa and Oji-Cree. The Dene´ are part of the larger Na-Dene language family which include Alaskan Gwich’in and the American Apache and Navaho peoples. The Denesuline are a distinct group of Dene.