Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Abstract

Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…42 This is partially independent of IFN-g and appears to be associated with IL-17-driven granuloma formation. 42,43 Immune protection in Mtb infection is certainly multifaceted; for example, we show here that IL-7 decreased in NHP PBMCs IL-10 and Foxp3 gene expression, whereas only IL-7, yet not IFN-g yielded increased IL-17 gene and protein expression in PBMCs from 5/5 NHPs (Figure 2). Thus, increased IL-17 protein detection in situ and IL-7-driven IL-17 production in vitro suggest that the 6 exonspanning IL-7 protein mediates beneficial effects in Mtb infection via IL-17 induction.…”

Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor

“…Inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-g and IL-17A responses (50). IL-17A participates in the protection against M. tuberculosis after vaccination (20) and in the formation of the mycobacterial granuloma (18,19). However, IL-17A is a highly inflammatory cytokine implicated in a number of chronic inflammatory diseases, including TB, and it may be responsible for substantial tissue damage in the host (22).…”

“…IL-17A controls granulopoiesis and neutrophil recruitment to sites of inflammation, and is another important player in the context of mycobacterial infections. It is required for granuloma formation after either BCG or M. tuberculosis infection in the mouse (18,19). Th17 memory cells are involved in vaccine-induced protection against M. tuberculosis infection via the rapid recruitment of activated Th1 cells to the lung (20).…”

Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of Mycobacterium avium Complex Disease

“…Th17 cells accelerate the accumulation of Th1 cells and enhance Th1 antimycobacterial responses (33)(34)(35). IL-17 also plays a role in the formation and maintenance of granuloma in mycobacteria-infected lungs (36,37). However, re-exposure of tuberculosis-infected mice to high levels of tuberculosis Ag promotes further Th17 responses that cause extensive lung damage associated with elevated neutrophil recruitment (38).…”