IL-15 has substantial potential as an immunotherapeutic agent for augmenting immune responses. However, the activity of IL-15 is mediated by a unique mechanism in which the cytokine is transpresented by cell-bound high-affinity IL-15Rα to target cells expressing the IL-15Rβ and the common γ-chain. Thus, the efficacy of administered IL-15 alone may be limited by the availability of free IL-15Rα. We now show that administration of soluble IL-15/IL-15Rα complexes greatly enhanced IL-15 half-life and bioavailability in vivo. Treatment of mice with this complex, but not with IL-15 alone, resulted in robust proliferation of memory CD8 T cells, NK cells, and NK T cells. The activity of the complex required IL-15Rβ, but not IL-15Rα, expression by the responding cells and was IL-7-independent. Interestingly, IL-15/IL-15Rα immunotherapy also caused naive CD8 T cell activation and development into effector cells and long-term memory T cells. Lastly, complexed IL-15, as compared with IL-15 alone, dramatically reduced tumor burden in a model of B16 melanoma. These findings hold significant importance for the use of IL-15 as a potential adjuvant/therapeutic and inducer of homeostatic proliferation, without the necessity for prior immunodepletion.

T cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs. CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells. CCR6-deficient DCs were unable to respond to bacterial invasion of PPs and failed to initiate T cell activation, resulting in reduced defense against oral infection. Thus, CCR6-dependent regulation of DCs is responsible for localized T cell dependent defense against entero-invasive pathogens.

Both CD4+ T cell help and IL-2 have been postulated to "program" activated CD8 + T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8 + T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4 + T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8 + T cells peaked 3-4 days after initial priming and was dependent on CD4 + T cell help, likely through a CD28:CD80/86 mediated pathway. CD4 + T cell or CD25-deficiency led to normal early effector CD8 + T cell differentiation, but a subsequent lack of accumulation of CD8 + T cells resulting in overall decreased memory cell generation. Interestingly, in both primary and recall responses KLRG1 high CD127 low short-lived effector cells were drastically diminished in the absence of IL-2 signaling, although memory precursors remained intact. In contrast to previous reports, upon secondary antigen encounter CD25-deficient CD8 + T cells were capable of undergoing robust expansion, but short-lived effector development was again impaired. Thus, these results demonstrated that CD4 + T cell help and IL-2 signaling were linked via CD25 up-regulation, which controls the expansion and differentiation of antigen-specific effector CD8 + T cells, rather than "programming" memory cell traits.infection | memory

Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging impacts on both hematopoietic and non-hematopoietic cell lineages, including dendritic cells (DCs), basophils, eosinophils, mast cells, CD4+, CD8+ and natural killer (NK) T cells, B cells and epithelial cells. While TSLP's role in the promotion of TH2 responses has been extensively studied in the context of lung- and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems, including the blockade of TH1/TH17 responses and the promotion of cancer and autoimmunity. This review will highlight recent advances in the understanding of TSLP signal transduction, as well as the role of TSLP in allergy, autoimmunity and cancer. Importantly, these insights into TSLP's multifaceted roles could potentially allow for novel therapeutic manipulations of these disorders.

Dendritic cells (DCs) are a critical player in immune responses, linking innate and adaptive immunity. We show here that DC-specific deletion of the STAT5 was not critical for development, but was required for type-2, but not type-1, allergic responses in both the skin and lung. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of costimulatory molecules and chemokine production. Furthermore, type-2 responses in mice with DC-specific loss of STAT5resembled those seen in TSLPR-deficient mice. These results show that the TSLP- STAT5 axis in DCs is a critical component for the promotion of type-2 immunity at barrier surfaces.

Despite the recognized role of the T-bet transcription factor in the differentiation of Th1 cells, T-bet-deficient mice can develop small numbers of IFN-γ-producing CD4 T cells. Although these are not sufficient to allow normal handling of some pathogens, T-bet-deficient mice do resolve infection with the intracellular pathogen Listeria monocytogenes. In contrast, we report that expression of T-bet is required for resistance to Salmonella infection. T-bet-deficient mice succumbed to infection with attenuated Salmonella and did not generate IFN-γ-producing CD4 T cells or isotype-switched Salmonella-specific Ab responses. Spleen cells from Salmonella-infected T-bet-deficient mice secreted increased levels of IL-10, but not IL-4, upon in vitro restimulation. A Salmonella-specific TCR transgenic adoptive transfer system was used to further define the involvement of T-bet expression in the development of Salmonella-specific Th1 cells. Wild-type Salmonella-specific CD4 T cells activated in T-bet-deficient recipient mice displayed no defect in clonal expansion, contraction, or IFN-γ production. In contrast, T-bet-deficient, Salmonella-specific CD4 T cells activated in wild-type recipient mice produced less IFN-γ and more IL-2 upon in vivo restimulation. Therefore, expression of T-bet by CD4 T cells is required for the development of Salmonella-specific Th1 cells, regulation of IL-10 production, and resistance to Salmonella infection.

Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of antigen. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as ILC1 contains CD4+ CD8−, CD4− CD8+ and CD4− CD8− populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4+ ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4+ ILC1 and NKp44+ ILC3, but not CD4− ILC1 or ILC2, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology as well as immune dysregulation. Furthermore, we demonstrate that CD4+ and CD4− ILC1 are functionally divergent based on their IL-6Rα expression, and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4+ and CD4− ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases such as systemic sclerosis.

Interleukin-15 (IL-15) plays a multifaceted role in immune homeostasis, but the unreliability of IL-15 detection has stymied exploration of IL-15 regulation in vivo. To visualize IL-15 expression, we created a transgenic mouse expressing emerald-GFP (EmGFP) under IL-15 promoter control. EmGFP/IL-15 was prevalent in innate cells including dendritic cells (DCs), macrophages, and monocytes. However, DC subsets expressed varying levels of EmGFP/IL-15 with CD8+ DCs constitutively expressing EmGFP/IL-15 and CD8− DCs expressing low EmGFP/IL-15 levels. Virus infection resulted in IL-15 upregulation in both subsets. By crossing the transgenic mice to mice deficient in specific elements of innate signaling, we found a cell-intrinsic dependency of DCs and Ly6C+ monocytes on IFNAR expression for EmGFP/IL-15 upregulation after VSV infection. In contrast, myeloid cells did not require the expression of MyD88 to upregulate EmGFP/IL-15 expression. These findings provide evidence of previously unappreciated regulation of IL-15 expression in myeloid lineages during homeostasis and following infection.