Innate lymphoid cell regulation of adaptive immunity

Innate lymphoid cells (ILCs) were identified principally as non‐T‐cell sources of key cytokines, able to provide rapid and early production of these molecules in the support of tissue homeostasis, repair and response to infection. As our understanding of these cells has developed, it has become evident that ILCs can impact on lymphocytes through a range of mechanisms. Hence, an exciting area of research has evolved in determining the extent to which ILCs may regulate adaptive immune responses. This review will focus initially on our current understanding of where ILC populations are located and what this means for potential cellular interactions. Mechanisms underpinning such interactions and how they may contribute to controlling adaptive immunity will then be considered

MHC-II: A Mutual Support System for ILCs and T Cells?

Innate and adaptive immune cells form an ongoing partnership during an immune response. In this issue of Immunity, Oliphant et al. (2014) show that MHC class II-peptide presentation by group 2 innate lymphoid cells is needed for reciprocal regulation of both cell types, resulting in effective antihelminth immunity

Lymphoid Tissue Inducer Cells: Pivotal Cells in the Evolution of CD4 Immunity and Tolerance?

Phylogeny suggests that the evolution of placentation in mammals was accompanied by substantial changes in the mammalian immune system: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi) are members of an emerging family of innate lymphoid cells (ILCs) that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3 dependent regulatory T (Tregs) cells that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the Tregs that under normal circumstances are absolutely required to regulate CD4 effector cells

Type II Bi 1- x W x O 1.5 + 1.5 x : a (3 + 3)-dimensional commensurate modulation that stabilizes the fast- ion conducting delta phase of bismuth oxide

The Type II phase in the Bi1 xWxO1.5 + 1.5x system is shown to have a (3 + 3)- dimensional modulated -Bi2O3-related structure, in which the modulation vector " ‘locks in’ to a commensurate value of 1/3. The structure was refined in a 3 3 3 supercell against single-crystal Laue neutron diffraction data. Ab initio calculations were used to test and optimize the local structure of the oxygen sublattice around a single mixed Bi/W site. The underlying crystal chemistry was shown to be essentially the same as for the recently refined (3 + 3)-dimensional modulated structure of Type II Bi1 xNbxO1.5 + x (Ling et al., 2013), based on a transition from fluorite-type to pyrochlore-type via the appearance of W4O18 ‘tetrahedra of octahedra’ and chains of corner-sharing WO6 octahedra along h110iF directions. The full range of occupancies on this mixed Bi/W site give a hypothetical solid-solution range bounded by Bi23W4O46.5 (x = 0.148) and Bi22W5O48 (x = 0.185), consistent with previous reports and with our own synthetic and analytical results

Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology

The discovery of Th17 cell plasticity, in which CD4 + IL-17-producing Th17 cells give rise to IL-17/IFN-γ double-producing cells and Th1-like IFNγ+ ex-Th17 lymphocytes, has raised questions regarding which of these cell types contribute to immunopathology during inflammatory diseases. In this study, we show using Helicobacter hepaticus-induced intestinal inflammation that IL-17ACre- or Rag1Cre-mediated deletion of Tbx21 has no effect on the generation of IL-17/IFN-g double-producing cells, but leads to a marked absence of Th1-like IFNγ+ ex-Th17 cells. Despite the lack of Th1-like ex-Th17 cells, the degree of H. hepaticus-Triggered intestinal inflammation in mice in which Tbx21 was excised in IL-17-producing or Rag1-expressing cells is indistinguishable from that observed in control mice. In stark contrast, using experimental autoimmune encephalomyelitis, we show that IL-17ACre-mediated deletion of Tbx21 prevents the conversion of Th17 cells to IL-17A/IFN-γ double-producing cells as well as Th1-like IFN-γ+ ex-Th17 cells. However, IL-17ACre-mediated deletion of Tbx21 has only limited effects on disease course in this model and is not compensated by Ag-specific Th1 cells. IL-17ACre-mediated deletion of Rorc reveals that RORγt is essential for the maintenance of the Th17 cell lineage, but not immunopathology during experimental autoimmune encephalomyelitis. These results show that neither the single Th17 subset, nor its progeny, is solely responsible for immunopathology or autoimmunity

ICOS is required for the generation of both central and effector CD4⁺ memory T-cell populations following acute bacterial infection

Interactions between ICOS and ICOS ligand (ICOSL) are essential for the development of T follicular helper (Tfh) cells and thus the formation and maintenance of GC reactions. Given the conflicting reports on the requirement of other CD4(+) T‐cell populations for ICOS signals, we have employed a range of in vivo approaches to dissect requirements for ICOS signals in mice during an endogenous CD4(+) T‐cell response and contrasted this with CD28 signals. Genetic absence of ICOSL only modestly reduced the total number of antigen‐specific CD4(+) T cells at the peak of the primary response, but resulted in a severely diminished number of both T central memory and T effector memory cells. Treatment with blocking anti‐ICOS mAb during the primary response recapitulated these effects and caused a more substantial reduction than blocking CD28 signals with CTLA4Ig. During the memory phase of the response further signals through ICOS or CD28 were not required for survival. However, upon secondary challenge only Tfh cell expansion remained heavily ICOS‐dependent, while CD28 signals were required for optimal expansion of all subsets. These data demonstrate the importance of ICOS signals specifically for memory CD4(+) T‐cell formation, while highlighting the potential of therapeutically targeting this pathway

Nutrient stripping: the global disparity between food security and soil nutrient stocks

1. The Green Revolution successfully increased food production but in doing so created a legacy of inherently leaky and unsustainable agricultural systems. Central to this are the problems of excessive nutrient mining. If agriculture is to balance the needs of food security with the delivery of other ecosystem services, then current rates of soil nutrient stripping must be reduced and the use of synthetic fertilisers made more efficient. 2. We explore the global extent of the problem, with specific emphasis on the failure of macronutrient management (e.g. nitrogen, phosphorus) to deliver continued improvements in yield and the failure of agriculture to recognise the seriousness of micronutrient depletion (e.g. copper, zinc, selenium). 3. Nutrient removals associated with the relatively immature, nutrient-rich soils of the UK are contrasted with the mature, nutrient-poor soils of India gaining insight into the emerging issue of nutrient stripping and the long-term implications for human health and soil quality. Whilst nutrient deficiencies are rare in developed countries, micronutrient deficiencies are commonly increasing in less-developed countries. Increasing rates of micronutrient depletion are being inadvertently accomplished through increasing crop yield potential and nitrogen fertiliser applications. 4. Amongst other factors, the spatial disconnects caused by the segregation and industrialisation of livestock systems, between rural areas (where food is produced) and urban areas (where food is consumed and human waste treated) are identified as a major constraint to sustainable nutrient recycling. 5. Synthesis and applications. This study advocates that agricultural sustainability can only be accomplished using a whole-systems approach that thoroughly considers nutrient stocks, removals, exports and recycling. Society needs to socially and environmentally re-engineer agricultural systems at all scales. It is suggested that this will be best realised by national-scale initiatives. Failure to do so will lead to an inevitable and rapid decline in the delivery of provisioning services within agricultural systems