InVivoMAb anti-mouse IL-2 (Clone: JES6-5H4)
Villegas-Mendez, A., et al. (2015). "Parasite-specific CD4+IFN-gamma+IL-10+ T cells distribute within both lymphoid and non-lymphoid compartments and are controlled systemically by IL-27 and ICOS during blood-stage malaria infection." Infect Immun. pii: IAI.01100-15. PubMed
Immune-mediated pathology in IL-10 deficient mice during blood-stage malaria infection typically manifests in non-lymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive non-lymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programmes in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual IFN-gamma-YFP and IL-10-GFP reporter mice we show that CD4+YFP+ T cells are the major source of IL-10 in both lymphoid and non-lymphoid compartments throughout the course of blood-stage P. yoelii infection. Mature splenic CD4+YFP+GFP+ T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the non-lymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4+YFP+GFP+ T cells from the liver and lung produced significantly higher quantities of IL-10 than their splenic counterparts, showing that the CD4+YFP+GFP+ T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete non-lymphoid and lymphoid organs, we show that IL-10 production by CD4+YFP+ T cells is controlled systemically during malaria infection through IL-27R signalling that is supported post-CD4+ T cell priming by ICOS signalling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive non-lymphoid organs.
Srivastava, S., et al. (2014). "Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection." J Exp Med 211(5): 961-974. PubMed
Regulatory T (T reg) cells play an essential role in preventing autoimmunity but can also impair clearance of foreign pathogens. Paradoxically, signals known to promote T reg cell function are abundant during infection and could inappropriately enhance T reg cell activity. How T reg cell function is restrained during infection to allow the generation of effective antiviral responses remains largely unclear. We demonstrate that the potent antiviral type I interferons (IFNs) directly inhibit co-stimulation-dependent T reg cell activation and proliferation, both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). Loss of the type I IFN receptor specifically in T reg cells results in functional impairment of virus-specific CD8(+) and CD4(+) T cells and inefficient viral clearance. Together, these data demonstrate that inhibition of T reg cells by IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection.
Gasteiger, G., et al. (2013). "IL-2-dependent adaptive control of NK cell homeostasis." J Exp Med 210(6): 1179-1187. PubMed
Activation and expansion of T and B lymphocytes and myeloid cells are controlled by Foxp3(+) regulatory T cells (T reg cells), and their deficiency results in a fatal lympho- and myeloproliferative syndrome. A role for T reg cells in the homeostasis of innate lymphocyte lineages remained unknown. Here, we report that T reg cells restrained the expansion of immature CD127(+) NK cells, which had the unique ability to up-regulate the IL2Ralpha (CD25) in response to the proinflammatory cytokine IL-12. In addition, we observed the preferential accumulation of CD127(+) NK cells in mice bearing progressing tumors or suffering from chronic viral infection. CD127(+) NK cells expanded in an IL-2-dependent manner upon T reg cell depletion and were able to give rise to mature NK cells, indicating that the latter can develop through a CD25(+) intermediate stage. Thus, T reg cells restrain the IL-2-dependent CD4(+) T cell help for CD127(+) immature NK cells. These findings highlight the adaptive control of innate lymphocyte homeostasis.
Gwyer Findlay, E., et al. (2013). "IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection." J Immunol 190(9): 4553-4561. PubMed
IL-27 exerts pleiotropic suppressive effects on naive and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4(+) T cell chemotactic responses, as a mechanism to reduce T cell-dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, proinflammatory infection, we demonstrate that IL-27R signaling represses chemotaxis of infection-derived splenic CD4(+) T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4(+) T cells from malaria-infected, IL-27R-deficient (WSX-1(-/-)) mice than from infected wild-type mice. We find that IL-27 signaling suppresses splenic CD4(+) T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4(+) T cell subtypes, including Th1 cells, and also by controlling the overall composition of the CD4(+) T cell compartment. Diminution of the Th1 response in infected WSX-1(-/-) mice in vivo by neutralization of IL-12p40 attenuated CCR5 expression by infection-derived CD4(+) T cells and also reduced splenic CD4(+) T cell chemotaxis toward CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4(+) T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.
Villegas-Mendez, A., et al. (2013). "IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals." PLoS Pathog 9(4): e1003293. PubMed
The IL-27R, WSX-1, is required to limit IFN-gamma production by effector CD4(+) T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1(+)) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4(+) T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1(-)/(-) and IL-10(-)/(-) mice and the numbers and phenotype of Foxp3(+) cells were largely unaltered in WSX-1(-)/(-) mice during infection. As expected, depletion of Foxp3(+) cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection.
Cho, H. I., et al. (2012). "A potent vaccination strategy that circumvents lymphodepletion for effective antitumor adoptive T-cell therapy." Cancer Res 72(8): 1986-1995. PubMed
Adoptive cell therapy using tumor-reactive T lymphocytes is a promising approach for treating advanced cancer. Successful tumor eradication depends primarily on the expansion and survival of the adoptively transferred T cells. Lymphodepletion using total body irradiation (TBI) and administering high-dose interleukin (IL)-2 have been used with adoptive cell therapy to promote T-cell expansion and survival to achieve maximal therapeutic effects. However, TBI and high-dose IL-2 increase the risk for major complications that impact overall survival. Here we describe an alternative approach to TBI and high-dose IL-2 for optimizing adoptive cell therapy, resulting in dramatic therapeutic effects against established melanomas in mice. Administration of a potent, noninfectious peptide vaccine after adoptive cell therapy dramatically increased antigen-specific T-cell numbers leading to enhancement in the survival of melanoma-bearing mice. Furthermore, combinations of peptide vaccination with PD1 blockade or IL-2/anti-IL-2 antibody complexes led to complete disease eradication and long-term survival in mice with large tumors receiving adoptive cell therapy. Our results indicate that PD1 blockade and IL-2/anti-IL-2 complexes enhance both the quantitative and qualitative aspects of the T-cell responses induced by peptide vaccination after adoptive cell therapy. These findings could be useful for the optimization of adoptive cell therapy in cancer patients without the need of toxic adjunct procedures.
Weber, K. S., et al. (2010). "Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization." J Immunol 185(5): 2836-2846. PubMed
Th cell subsets have unique calcium (Ca(2+)) signals when activated with identical stimuli. The regulation of these Ca(2+) signals and their correlation to the biological function of each T cell subset remains unclear. Trpm4 is a Ca(2+)-activated cation channel that we found is expressed at higher levels in Th2 cells compared with Th1 cells. Inhibition of Trpm4 expression increased Ca(2+) influx and oscillatory levels in Th2 cells and decreased influx and oscillations in Th1 cells. This inhibition of Trpm4 expression also significantly altered T cell cytokine production and motility. Our experiments revealed that decreasing Trpm4 levels divergently regulates nuclear localization of NFATc1. Consistent with this, gene profiling did not show Trpm4-dependent transcriptional regulation, and T-bet and GATA-3 levels remain identical. Thus, Trpm4 is expressed at different levels in Th cells and plays a distinctive role in T cell function by differentially regulating Ca(2+) signaling and NFATc1 localization.
Carlson, M. J., et al. (2009). "In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations." Blood 113(6): 1365-1374. PubMed
The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-alpha (TNF-alpha) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.