Modulation of naive CD4+ T cell activation and dendritic cell function in the lungs during pulmonary mycobacterial infection

Initiation of CD4+ T cell responses is critical for a successful host response against the intracellular pathogen Mycobacterium tuberculosis (MTB). Naive CD4+ T cells are activated by dendritic cells (DCs) that sample antigen in the periphery, upregulate chemokine receptor CCR7, and migrate to secondary lymphoid organs to encounter naive CD4+ T cells. Pulmonary mycobacterial infection with the attenuated strain, Mycobacterium bovis BCG is used as a model to study host immune responses in the lungs. During BCG infection, lung bacterial burden peaks 4-6 wks post-infection and declines to undetectable levels by 12-14 wks.;Inflammation caused by peak BCG infection (4-6 wks) led to enhanced naive CD4+ T cell responses directed against a model airway antigen, ovalbumin (OVA). BCG infection caused accumulation, activation, and proliferation of OVA-specific CD4+ T cells in lung and draining mediastinal lymph node (MLN). Compared to uninfected mice, infected mice had greater proliferation in lung and lymph node but only infected mice had detectable in situ proliferation of OVA-specific CD4+ T cells in the lungs. BCG-infection induced expression of CCL19 in the lungs; CCL19 is a CCR7 ligand and naive T cell chemoattractant. Lung inflammation, during infection, caused accumulation and maturation of lung DCs that could present peptide antigens ex vivo. OVA-specific CD4+ T cells from the lungs of infected mice were more likely to differentiate into effector T cells and produce IFN-gamma than T cells from uninfected mice.;BCG infection caused accumulation and maturation of DCs in infected lungs even as the mycobacterial burden declined. Lung DCs from infected mice expressed increased amounts of MHC-II but comparable amounts of CCR7 relative to uninfected mice. Gene expression of a CCR7 ligand, CCL19 progressively increased throughout BCG infection and the expression was MyD88-dependent. Lung CD11c+ cells from BCG-infected mice activated OVA-specific naive CD4+ T cells more than lung CD11c+ cells from uninfected mice. Therefore, our findings suggest that during BCG infection, inflammation and sustained expression of CCL19 recruit and retain mature DCs in the lung where they can activate naive CD4+ T cells.