Maintenance of Pulmonary Th1 Effector Function in Chronic Tuberculosis Requires Persistent IL-12 Production

Central memory CD4+ T cells provide a pool of lymph node-homing, Ag-experienced cells that are capable of responding rapidly after a secondary infection. We have previously described a population of central memory CD4+ T cells in Leishmania major-infected mice that were capable of mediating immunity to a secondary infection. In this study, we show that the Leishmania-specific central memory CD4+ T cells require IL-12 to produce IFN-γ, demonstrating that this population needs additional signals to develop into Th1 cells. In contrast, effector cells isolated from immune mice produced IFN-γ in vitro or in vivo in the absence of IL-12. In addition, we found that when central memory CD4+ T cells were adoptively transferred into IL-12-deficient hosts, many of the cells became IL-4 producers. These studies indicate that the central memory CD4+ T cell population generated during L. major infection is capable of developing into either Th1 or Th2 effectors. Thus, continued IL-12 production may be required to ensure the development of Th1 cells from this central memory T cell pool, a finding that has direct relevance to the design of vaccines dependent upon central memory CD4+ T cells.

Section: Discussionsupporting

confidence: 79%

The Central Memory CD4+ T Cell Population Generated duringLeishmania majorInfection Requires IL-12 to Produce IFN-γ

Pakpour

Zaph

Scott

2008

“…These findings are supported by a recent study using a murine model of tuberculosis. Reconstitution of M. tuberculosis-infected p40-deficient mice with rIL-12 only partially restored their ability to form granulomata (35). Granulomata were fewer in IL-12-reconstituted p40-deficient mice than in WT controls suggesting that IL-12 contributes in parts to granuloma formation and that other factors such as IL-23 are likely required for a sustained granulomatous inflammatory response (35).…”

Section: Discussionmentioning

confidence: 99%

IL-23 Enhances the Inflammatory Cell Response in Cryptococcus neoformans Infection and Induces a Cytokine Pattern Distinct from IL-12

Kleinschek

Müller

Brodie³

et al. 2006

206

144

IL-23, a heterodimeric cytokine composed of the p40 subunit of IL-12 and a novel p19 subunit, has been shown to be a key player in models of autoimmune chronic inflammation. To investigate the role of IL-23 in host resistance during chronic fungal infection, wild-type, IL-12- (IL-12p35−/−), IL-23- (IL-23p19−/−), and IL-12/IL-23- (p40-deficient) deficient mice on a C57BL/6 background were infected with Cryptococcus neoformans. Following infection, p40-deficient mice demonstrated higher mortality than IL-12p35−/− mice. Reconstitution of p40-deficient mice with rIL-23 prolonged their survival to levels similar to IL-12p35−/− mice. IL-23p19−/− mice showed a moderately reduced survival time and delayed fungal clearance in the liver. Although IFN-γ production was similar in wild-type and IL-23p19−/− mice, production of IL-17 was strongly impaired in the latter. IL-23p19−/− mice produced fewer hepatic granulomata relative to organ burden and showed defective recruitment of mononuclear cells to the brain. Moreover, activation of microglia cells and expression of IL-1β, IL-6, and MCP-1 in the brain was impaired. These results show that IL-23 complements the more dominant role of IL-12 in protection against a chronic fungal infection by an enhanced inflammatory cell response and distinct cytokine regulation.

“…Ϫ/Ϫ mice with rIL-12 for the first 4 wk of M. tuberculosis infection partially restored the deficient IFN-␥-secreting T cell response, leading to granuloma formation (33). However, withdrawal of the rIL-12 led to progressive infection, indicating that IL-12 is required for the maintenance of T cell immunity through the expansion of memory T cells.…”

Section: Treatment Of Il-12p40mentioning

confidence: 99%

Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses

Wozniak

Ryan

Britton

2006

Host control of Mycobacterium tuberculosis is dependent on the activation of CD4+ T cells secreting IFN-γ and their recruitment to the site of infection. The development of more efficient vaccines against tuberculosis requires detailed understanding of the induction and maintenance of T cell immunity. Cytokines important for the development of cell-mediated immunity include IL-12 and IL-23, which share the p40 subunit and the IL-12Rβ1 signaling chain. To explore the differential effect of IL-12 and IL-23 during M. tuberculosis infection, we used plasmids expressing IL-23 (p2AIL-23) or IL-12 (p2AIL-12) alone in dendritic cells or macrophages from IL-12p40−/− mice. In the absence of the IL-12/IL-23 axis, immunization with a DNA vaccine expressing the M. tuberculosis Ag85B induced a limited Ag-specific T cell response and no control of M. tuberculosis infection. Codelivery of p2AIL-23 or p2AIL-12 with DNA85B induced strong proliferative and IFN-γ-secreting T cell responses equivalent to those observed in wild-type mice immunized with DNA85B. This response resulted in partial protection against aerosol M. tuberculosis; however, the protective effect was less than in wild-type mice owing to the requirement for IL-12 or IL-23 for the optimal expansion of IFN-γ-secreting T cells. Interestingly, bacillus Calmette-Guérin immune T cells generated in the absence of IL-12 or IL-23 were deficient in IFN-γ production, but exhibited a robust IL-17 secretion associated with a degree of protection against pulmonary infection. Therefore, exogenous IL-23 can complement IL-12 deficiency for the initial expansion of Ag-specific T cells and is not essential for the development of potentially protective IL-17-secreting T cells.