Summary The importance of T helper type 1(Th1) immunity in host resistance to the intracellular bacterium Francisella tularensis is well established. However, the relative roles of Interleukin (IL)-12/Th1 and IL-23/T helper type 17(Th17) responses in immunity to F.tularensis have not been studied. The IL-23/Th17 pathway is critical for protective immunity against extracellular bacterial infections. In contrast, the IL-23/Th17 pathway is dispensable for protection against intracellular pathogens such as Mycobacteria. Our data show that the IL-23/Th17 pathway regulates the IL-12/Th1 pathway and is required for protective immunity against F.tularensis Live Vaccine Strain (LVS). We show that IL-17, but not IL-17F or IL-22 induces IL-12 production in dendritic cells and mediates Th1 responses. Furthermore, we show that IL-17 also induces IL-12 and IFNγ production in macrophages and mediates bacterial killing. Together, these findings illustrate a novel biological function for IL-17 in regulating IL-12/Th1 immunity and host responses to an intracellular pathogen.

CD70-mediated stimulation of CD27 is an important cofactor of CD4+ T cell licensed dendritic cells. However, it is unclear how CD70-mediated stimulation of T cells is integrated with signals that emanate from Signal 3 pathways, such as type-1 interferon (IFN-1) and IL-12. We find that while stimulation of CD27 in isolation drives weak EomesoderminhiT-betlo CD8+ T cell responses to OVA immunization, profound synergistic expansion is achieved by co-targeting TLR. This cooperativity can substantially boost anti-viral CD8+ T cell responses during acute infection. Concomitant stimulation of TLR significantly increases per-cell IFNγ-production and the proportion of the population with characteristics of short-lived effector cells, yet also promotes the ability to form long-lived memory. Notably, while IFN-1 contributes to the expression of CD70 on dendritic cells, the synergy between CD27 and TLR stimulation is dependent upon IFN-1’s effect directly on CD8+ T cells, and is associated with the increased expression of T-bet. Surprisingly, we find that IL-12 fails to synergize with CD27 stimulation to promote CD8+ T cell expansion, despite its capacity in driving effector differentiation. Together these data identify complex interactions between Signal 3 and costimulatory pathways, and identify opportunities to influence the differentiation of CD8+ T cell responses.

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Interferon-gamma (IFNγ) is essential for limiting Mycobacterium tuberculosis infection. Using the mouse model, we have recently shown that vaccination triggered accelerated Interleukin-17 (IL-17) and IFNγ responses by CD4+ T cells in the lung during M. tuberculosis aerosol challenge. We propose that vaccination induces IL-17- producing CD4+ T cells that populate the lung and, after challenge, trigger the production of chemokines. The induction of chemokines results in recruitment of IFNγ-producing CD4+ T cells from the lymphoid compartment and ultimately restricts bacterial growth. The differential ability of IL-17-producing memory cells to populate the lung compared to the IFN-γ-producing cells suggests that these two cell types differ in their ability to migrate in response to chemokines. In support of this, our data using adoptive transfer models and chemotaxis assays suggests that differential responsiveness to chemokines and retention in different organs may provide the basis for the differential tissue distribution of these two cell types. During progression from effector to memory T cells, we also show differential expression of activation markers on IL17-producing and IFNγ-producing T cells. This information will lead us to determine whether altering the nature of the lung-resident IL-17 producing population impacts protective efficacy of the recall response to M.tuberculosis challenge. This work was supported by AI075106-01 and Children's Hospital of Pittsburgh.