Lung Neutrophils Facilitate Activation of Naive Antigen-Specific CD4+ T Cells during Mycobacterium tuberculosis Infection

Abstract

Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node, and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously-published observations that: 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection; and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs, prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naïve M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role for neutrophils in DC-migration we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results reveal a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that make DCs more effective initiators of naïve CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis.

Cathepsin G and Neutrophil Elastase Contribute to Lung-Protective Immunity against Mycobacterial Infections in Mice

“…Recently published reports also suggested either direct or immunomodulatory roles for neutrophils in mycobacterial pathogen elimination (36)(37)(38)(39)(40)(41). In tuberculosis, a strict regulation of protective immune responses to mycobacterial challenge is important to limit excessive inflammatory responses, and hence, irreversible loss of lung structure and function (42).…”

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

“…Of interest, in our current study we find FimH exposure to have a minimal effect on neutrophil responses in the lung. On the other hand, a recent study has suggested that neutrophils may also promote T cell activation by enhancing antigen acquisition of APCs through increased formation of apoptotic bodies containing mycobacterial antigen [16,40]. Since human neutrophils exposed to type 1 fimbriated E. coli were found to have enhanced apoptosis [41], we cannot rule out that in vivo FimH administration may have increased neutrophil apoptosis, thus enhancing the antigen acquisition capabilities of DCs.…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…Infected DC assisted by neutrophils (Abadie et al, 2005;Blomgran & Ernst, 2011) migrate to the lymph nodes and initiate T cell response. Due to a high production of IL-12, the response is largely polarized towards a Th1 type.…”

“…Neutrophils are involved in the formation of granuloma (Seiler et al, 2003) and in the initiation of T cell response: they were shown to transport live mycobacteria from peripheral tissues to the lymphoid organs and to deliver mycobacterial antigens to DC in a form that makes DC more effective initiators of naïve CD4 + T cell activation (Abadie et al, 2005;Blomgran et al, 2011). …”