Antigen presentation is crucial for the immune system to detect pathogens such as Mycobacterium tuberculosis (Mtb) and prime T cells for an immune response. MHC class I-related (MR1) molecule presents Mtb-derived riboflavin metabolites and induces production of IFN-γ and TNF-α by MR1-restricted T cells. Cellular mechanisms of MR1 antigen presentation from the endoplasmic reticulum to the cell surface using small ligands are well-defined. However, we have defined a role for trafficking of the MR1 molecule within endosomal compartments during intracellular microbial infection. Our lab has identified a unique role of calcium signaling in MR1 antigen presentation of Mtb, suggesting a role of calcium-sensing proteins in translocating the MR1-Mtb antigen complex to the cell surface. Synaptotagmins (Syts) are calcium-sensing membrane trafficking proteins that mediate vesicle fusion and exocytosis. Using IFN-γ release from human MR1-restriced T cells as an indicator, I found a 50% and 34% reduction in MR1 antigen presentation of Mtb when Syt1 and Syt7 was knocked out in airway epithelial BEAS-2B cells. Moreover, knocking out both Syt1 and Syt7 showed an interdependent relationship in regulating MR1 antigen presentation of Mtb. Interestingly, live-cell imaging showed that Syt1 and Syt7 co-localizes with lysosomes (Lamp1) and vesicles containing MR1 (Syt1: 55% and Syt7: 64%) and Mtb, indicating their potential role in the antigen loading of MR1 and/or translocation of loaded MR1 to the cell surface. The binding partners of Syt1 and Syt7 are synaptosome-associated protein (SNAP) 25 and SNAP23, respectively, for synaptic vesicle exocytosis. Knocking out SNAP23 in BEAS-2B cells showed a 75% reduction in presentation of Mtb and a 56% decrease in MR1 surface expression when induced with 6-formylpterin. These findings elucidate a potential mechanism that Syts regulate MR1 antigen presentation of Mtb by closely interacting with their SNAP binding partner.