NKG2D-Dependent IL-17 Production by Human T Cells in Response to an Intracellular Pathogen

Abstract

We studied the factors that control IL-17 production in human Mycobacterium tuberculosis infection. CD4+ cells from healthy tuberculin reactors produced IL-17 in response to autologous M. tuberculosis-stimulated monocytes, and most IL-17+ cells were Ag experienced, CD4+CD62L−. IL-17 production by CD4+ cells was inhibited by anti-IL-23, but not by Abs to IL-1, IL-6, or TGF-β. Anti-NKG2D reduced IL-17 production and the frequency of CD4+CD62− IL-17+ cells, suggesting that NKG2D stimulates IL-17 production. CD4+NKG2D+ cells did not produce IL-17. Monocytes and alveolar macrophages from healthy donors produced IL-23 in response to M. tuberculosis. Addition of CD4+ cells markedly enhanced IL-23 production by M. tuberculosis-stimulated monocytes, and this was inhibited by anti-NKG2D and by Abs to UL-16 binding protein (ULB)1, a ligand for NKG2D on APCs. We conclude that binding of NKG2D to UL-16 binding protein (ULB)1 contributes to IL-23-dependent IL-17 production by CD4+ cells in human M. tuberculosis infection.

Reduced Th17 Response in Patients with Tuberculosis Correlates with IL-6R Expression on CD4+T Cells

“…This was further supported by the finding that M. tuberculosis products down-regulate IL-6R expression on CD4 1 T cells in vitro. However, this may be challenged by the report by Paidipally and colleagues (20), which indicated that, in individuals with M. tuberculosis infection, IL-6 is not required for T cells to produce IL-17 in response to mycobacterial antigens. Nevertheless, the expansion of antigen-experienced Th17 cells evaluated by Paidipally and colleagues is different from differentiation of Th17 subsets from naive T cells-a process in which IL-6R-mediated signaling is required.…”

“…Although other mechanisms, such as the inhibitory functions of Th1 and Th2 cytokines, as well as nature killer group 2D (NKG2D) expressed on CD4 1 T cells, may be involved in regulating Th17 responses in M. tuberculosis infection, these are mostly related to regulation of the differentiated antigenspecific, but not nonspecific, Th17 responses (20,21,35,36). Our finding, that down-regulation of IL-6R expression on CD4 1 T cells in patients with active TB diseases, suggests that it may be an important mechanism driving the suppressed, nonspecific Th17 responses in patients with TB.…”

“…Th17 cells have been reported to play a central role, not only in the development of autoimmune and inflammatory diseases (12)(13)(14), but also in protection against intracellular pathogens (15,16). Although initial studies suggested that gd T cells are a primary source of IL-17 in response to M. tuberculosis infection (17,18), recent studies have indicated that Th17 cells are the major IL-17-producing cells and participate in the protective immunity against M. tuberculosis (9,(19)(20)(21)(22). Khader and colleagues (9,23) reported an indirect role for the Th17 response in protective immunity in mouse models of M. tuberculosis infection.…”

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

“…An increase of mycobacterial Ag-specific IL-17A production was reported in peripheral blood of healthy tuberculosis contacts (49) or tuberculin-positive individuals (50). Furthermore, an increase of IL-17A-producing TCR gd T cells was reported in peripheral blood of patients with tuberculosis (51).…”

Influence of interleukin-17 gene polymorphisms on the development of pulmonary tuberculosis

“…Increasing studies have reported that Th17 cells are the main IL-17-producing cells and contribute to protective immunity against Mycobacterium tuberculosis (Khader et al, 2007;Chen et al, 2009;Paidipally et al, 2009). Khader et al (2007) reported that Th17 response had a role in protective immunity in M. tuberculosis infection, and M. tuberculosis infection was correlated with a decreased Th17 response because of suppressing Th1 cytokines (Khader et al, 2007).…”