Abstract
Mycolic acid (MA), a major lipid component of Mycobacterium tuberculosis (Mtb) cell wall, can be presented by the non-polymorphic antigen presenting molecule CD1b to T cells isolated from Mtb-infected individuals. These MA-specific CD1b-restricted T cells are cytotoxic, produce Th1 cytokines, and form memory populations, suggesting that MA can be explored as a potential subunit vaccine candidate for TB. However, the controlled elicitation of MA-specific T cell responses has been challenging due to difficulties in the targeted delivery of lipid antigens and a lack of suitable animal models. In this study, we generated MA-loaded micellar nanocarriers (MA-Mc) comprised of self-assembled poly(ethylene glycol)-bl-poly(propylene sulfide; PEG-PPS) copolymers conjugated to an acid sensitive fluorophore to enhance intracellular delivery of MA to phagocytic immune cells. Using humanized CD1 transgenic (hCD1Tg) mice, we found these nanobiomaterials to be endocytosed by bone marrow-derived dendritic cells (DCs) and localized to lysosomal compartments. Additionally, MA-Mc demonstrated superior efficacy over free MA in activating MA-specific TCR transgenic (DN1) T cells in vitro. Following intranasal immunization, MA-Mc were primarily taken up by alveolar macrophages and DCs in the lung and induced activation and proliferation of adoptively transferred DN1 T cells. Furthermore, intranasal immunization with MA-Mc induced MA-specific T cell responses in the lungs of hCD1Tg mice. Collectively, our data demonstrates that pulmonary delivery of MA via PEG-PPS micelles to DCs can elicit potent CD1b-restricted T cell responses both in vitro and in vivo and MA-Mc could be explored as subunit vaccines against Mtb infection.
Highlights
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest communicable diseases [1]
The hydrodynamic diameter of MAloaded acid-sensitive fluorophore-conjugated micelles (MAASMc) was measured by dynamic light scattering (DLS) to be 68 nm, a size comparable to the unloaded vehicle (V-ASMc), with a zeta potential of −16.5 (Figure 1C,Table 1)
The loading of mycolic acid (MA) led to a 30% decrease in the fluorescence intensity of mycolic acidloaded acid sensitive fluorophore micelle (MA-ASMc) compared to V-ASMc (Figure 1D), and this decrease was consistent in solutions with pH values of 4 and above (Figure S2B)
Summary
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest communicable diseases [1]. MA broadly distributed within endosomal compartments of dendritic cells and MA-specific CD1b-restricted T cells can be detected in the blood [2] and disease sites of tuberculosis patients and demonstrated a memory response upon ex vivo re-stimulation [10]. Adoptive transfer of MA-specific CD1b-restricted T cells confers protection to Mtb infection in a human group 1 CD1 transgenic (hCD1Tg) mouse model [13, 14]. These data suggest that MA may be harnessed as components of novel vaccines against Mtb infection
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