Highlights d Mycobacterial granulomas contain a subpopulation of VEGF-A-producing macrophages d VEGF-A recruits macrophages to the granuloma via a nonangiogenic pathway d VEGF-A inhibition reduces granulomatous inflammation with limited effect on protection d Mice with myeloid-specific deletion of VEGF-A are more resistant to Mtb infection

Granulomatous inflammation is characteristic of many autoimmune and infectious diseases. The lymphatic drainage of these inflammatory sites remains poorly understood, despite an expanding understanding of lymphatic role in inflammation and disease. Here, we show that the lymph vessel growth factor Vegf-c is up-regulated in Bacillus Calmette-Guerin- and Mycobacterium tuberculosis-induced granulomas, and that infection results in lymph vessel sprouting and increased lymphatic area in granulomatous tissue. The observed lymphangiogenesis during infection was reduced by inhibition of vascular endothelial growth factor receptor 3. By using a model of chronic granulomatous infection, we also show that lymphatic remodeling of tissue persists despite resolution of acute infection and a 10- to 100-fold reduction in the number of bacteria and tissue-infiltrating leukocytes. Inhibition of vascular endothelial growth factor receptor 3 decreased the growth of new vessels, but also reduced the proliferation of antigen-specific T cells. Together, our data show that granuloma-up-regulated factors increase granuloma access to secondary lymph organs by lymphangiogenesis, and that this process facilitates the generation of systemic T-cell responses to granuloma-contained antigens.

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The World Health Organization declared a tuberculosis (TB) global emergency. Central nervous system (CNS) TB is a rare, highly devastating manifestation of extra-pulmonary TB. To date, research has focused on pulmonary TB, with no significant advancements being made in understanding the mechanisms associated with CNS TB. This study uses a small animal model of CNS TB that permits us to investigate the immune responses following CNS Mycobacterium tuberculosis (Mtb) infection. We use intracranial infection of mice with the H37Rv strain of Mtb which has been fluorescently tagged with a TdTomato plasmid, allowing us to track it in vivo, and analyzed the cellular composition of the subsequent immunological response in the brain. At 7 days post infection (PI), we show a robust infiltration of immune cells into the CNS including the infiltration of CD11c+ dendritic cells. We can also see Mtb-containing granuloma-like lesions. We adoptively transferred Mtb-specific P25 CD4+ T and found that these cells also accumulate in the brain and were found activated in the peripheral lymphoid tissue, including the spleen and cervical draining lymph nodes. The P25 T cells present in the brain display extensive proliferation. Moreover, P25 T cells present in the peripheral lymphoid organs of Mtb infected mice show increased proliferation when compared to non-infected controls suggesting a systemic sampling of CNS Mtb antigen. We also show that at 7 days PI there is a significantly higher percentage of activated, INFγ producing, CD4+ T in the brain. Both INFγ and IL-17 producing T cell populations increase in size by day 21. This study will provide knowledge into the pathogenesis of CNS TB, and provide possible treatment strategies to lessen its destructive outcome.

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