A major focus of this year's work was on innate defense mechanisms in mycobacterial infection. Although IL-12/23p40 is known to play an important role in host resistance to Mycobacterium spp, the cellular source, tissue localization, and regulation of p40 production during mycobacterial infection in vivo has been unclear. In a project completed and published this year, we used IL-12/23p40eYFP (yet40) reporter mice to track expression of the cytokine following Mycobacterium bovis bacillus Calmette-Gurin (BCG) infection. We found that in spleens of these mice, p40 production is initiated by a transient burst from CD11b(low)CD11c(+) dendritic cells (DC) which are later replaced at the onset of granuloma formation by CD11b(high)CD11c(+) DC as the major source of the cytokine. The latter subset was also found to be the key producer of DC-derived p40 in nonlymphoid tissue and in both spleen and liver optimal production of the cytokine was regulated by endogenous TNF-alpha. Although BCG and p40-expressing DC were both observed in splenic white pulp, p40(+) DC rarely colocalized with bacilli. Indeed, in vitro flow cytometry and confocal microscopy indicated that the presence of intracellular bacteria is not required for p40 production by DC and Transwell experiments confirmed that soluble mycobacterial components are sufficient for inducing cytokine expression by these cells. Moreover, when stimulated with LPS, DC directly infected with BCG showed impaired IL-12p40 production in vitro. Together, our findings establish CD11b(high) DC as a major source of IL-12/23p40 during mycobacterial infection in situ and implicate both soluble mycobacterial products and TNF-alpha in stimulating sustained production of p40 by these cells. In related work we have been continuing our studies on the role of the Toll-like receptor (TLR)/IL-1R signaling pathway in host resistance to Mycobacterium tuberculosis. To investigate the respective contributions of TLR versus IL-1 mediated signals in MyD88 dependent control of Mtb, we directly compared the outcome of Mtb infection in MyD88, Trif/MyD88, IL-1R1 and IL-1 beta -deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1beta signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and Trif/MyD88 -deficient mice, rather than being defective in IL-1 beta expression, displayed increased cytokine levels relative to WT animals. Similarly, infected mice deficient in Caspase-1 and ASC which have critical functions in inflammasome mediated IL-1 beta maturation, showed unimpaired IL-1 beta production and importantly, in contrast to IL-1 beta deficient mice survived acute infection. These findings, while demonstrating a major role for IL-1beta in host resistance to M. tuberculosis, reveal that in this infection expression of the cytokine involves a novel pathway, that is independent of both TLR signaling and Caspase-1 activation.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$892,059
Indirect Cost
City
State
Country
Zip Code
Moreira-Teixeira, LĂșcia; Mayer-Barber, Katrin; Sher, Alan et al. (2018) Type I interferons in tuberculosis: Foe and occasionally friend. J Exp Med 215:1273-1285
Kawabe, Takeshi; Zhu, Jinfang; Sher, Alan (2018) Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity? Nat Rev Immunol 18:1
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Iwamura, Chiaki; Bouladoux, Nicolas; Belkaid, Yasmine et al. (2017) Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood 129:171-176
Arbore, Giuseppina; West, Erin E; Spolski, Rosanne et al. (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4? T cells. Science 352:aad1210
Sher, Alan (2016) A Third signal from Conditioned DCs dictates microbial effector choice. Nat Rev Immunol 16:721
Riteau, Nicolas; Radtke, Andrea J; Shenderov, Kevin et al. (2016) Water-in-Oil-Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6-Dependent Pathway. J Immunol 197:3884-3893
Poholek, Amanda C; Jankovic, Dragana; Villarino, Alejandro V et al. (2016) IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Sci Immunol 1:

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