MycoLipid – the interaction of mycobacterial lipids with the cellular immune system governs granuloma formation and maintenance
Final Report Abstract
The lack of appropriate techniques and models has so far hampered the elucidation of the role and function of mycobacteria-specific, lipid-reactive T-cells. We have developed the guinea pig as a suitable small animal model to induce and study lipid-specific, adaptive immune responses and in parallel monitor bacteria-induced pathological changes in situ. We hypothesized that lipid-specific immune cells contribute to immune protection against Mycobacterium tuberculosis (Mtb) by instructing the formation and maintenance of granulomas. Lipid-reactive T-cells recognize their cognate lipid antigen in the context of type-1-CD1-molecules. Guinea pigs functionally express type-1-CD1-molecules and were used as a small animal model in the current study. Animals were vaccinated with the live-attenuated vaccine strain BCG or highly-purified, liposome-formulated phosphatidylinositol-hexa-mannoside (PIM6). PIM6-specific T-cell-responses were observed both after BCG- and PIM6-vaccination. The cellular response was significantly reduced in the presence of CD1b-blocking antibodies, indicating that a predominant part of this reactivity was CD1brestricted. While BCG-immunized animals responded to the full range of mycobacterial antigens, PIM6 immunization induced a lipid-focused immune response. This allowed to study the specific effect of lipidreactive T-cells on the course of infection after challenge with virulent Mtb. After the challenge, BCG- and PIM6-vaccinated animals showed significantly reduced pathology, smaller necrotic granulomas in lymph node and spleen and overall reduced bacterial loads. Comprehensive histological and transcriptional analyses in the draining lymph node revealed that protected animals showed reduced transcription-levels of inflammatory cyto- and chemokines and higher levels of CD1b-expression compared to controls. In protected animals, CD1b-expressing cells were predominantly observed in subcapsular areas of draining lymph nodes. The lymph from the tributary region enters the lymph node parenchyma via these subcapsular areas. It may be that the subcapsular CD1b-expressing cells take up lymph-borne lipids and present them to CD1b-restricted T-cells. Hence, the CD1-T-cell-axis could represent a vigilance system that responds to lipid antigens in the lymph and recruits additional immune cells to infected tissues. Along this line, we observed a close correlation between the number of T-cells infiltrating the injection-site-granuloma and the number of CD1b1-expressing cells in the lymph node. Our observations in the guinea pig model suggest that CD1b-restricted, PIM6-reactive T-cells contribute to granuloma integrity and immune-mediated containment of virulent Mtb.
Publications
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Animal models for human group 1 CD1 protein function. Molecular Immunology, 130, 159-163.
Eckhardt, Emmelie & Bastian, Max
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CD1-MR1 EMBO workshop: Beyond MHC-restricted lymphocytes, Oxford September 2019. Molecular Immunology, 134, 170-171.
Klenerman, Paul; Ogg, Graham & Salio, Mariolina
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Meeting report: 6th Global Forum on Tuberculosis Vaccines, 22–25 February 2022, Toulouse, France. Vaccine: X, 13, 100267.
Young, Carly; Suliman, Sara; Rozot, Virginie & Mendelsohn, Simon C.
