Research Highlights

A new light on migration

It has been long suspected that T cells migrate through uninflamed tissues as part of normal recirculation, but this has been difficult to demonstrate without the use of some traumatic procedure. Now in the Journal of Clinical Investigation, Kabashima and colleagues use a new system that can follow the migration of cells of the immune response between skin and draining lymph nodes with only minimal intervention. Transgenic mice ubiquitously expressing the coral-derived protein Kaede permanently convert to red fluorescence after exposure to violet light. With this system, the authors observe steady-state trafficking to draining lymph nodes by T cells, especially regulatory T cells (T_reg cells). This migration is enhanced during a cutaneous immune reaction in which T_reg cells constitute a disproportionate number of the T cells. T_reg cells migrating from the skin demonstrate superior regulation mediated by their in situ increase in suppressive molecules. This system should allow accurate characterization of cells in vivo with minimal intervention. ZF

J. Clin. Invest. (1 March 2010) doi:10.1172/JCI40926

Modeling coinfection

Under natural conditions, viral and bacterial coinfection commonly occurs, but experimental systems have tended to look at infection in isolation. Now, in Cell Host and Microbe, Medzhitov and colleagues use a model of influenza and listeria challenge to study the host response during coinfection. Preinfection of lungs with influenza impairs a subsequent response to listeria, which results in a higher bacterial burden and lower inflammatory cytokine production. This impairment is attributed to generalized production of glucocorticoid, a well known stress hormone and immunosuppressant. Although preventing this stress response improves bacterial clearance, it has the side effect of increasing morbidity through an overexuberant immune response. Therefore, coinfection represents a complex interaction, with the stress response being an important modulator of immunopathology. ZF

Cell Host Microbe (18 Feb 2010) doi:10.1016/j.chom.2010.01.010

New players in type 2 immunity

Interleukin 25 (IL-25) is a cytokine associated with T helper type 2 (T_H2) cell responses. In Nature, two groups show that IL-25 controls the induction of cell types linked to type 2 immunity. Artis and colleagues describe that IL-25 promotes the accumulation of a lineage-negative multipotent progenitor population present in the gut-associated lymphoid tissue. IL-4⁻c-Kit^int progenitor cells give rise to macrophages, mast cells and basophils that function as competent antigen-presenting cells, promote T_H2 cytokine responses and protect against helminth infection. McKenzie and colleagues show that IL-25 and IL-33 act together in the spleen and mesenteric lymph nodes to expand a previously unknown innate effector cell called the 'nuocyte'. Nuocytes are the main early source of IL-13 during helminth infection and are essential for worm expulsion. These findings describe previously unknown immune pathways that promote T_H2 responses. IV

Nature (3 March 2010) doi:10.1038/nature08901; doi:10.1038/nature08900

Inhibiting suppression

In T_reg cells, T cell antigen receptor signaling can inhibit T_reg cell–mediated suppression. In Science, Dustin and colleagues show that the kinase PKC-θ mediates such a T cell antigen receptor–induced negative feedback loop. Inhibition of PKC-θ enhances the suppressive functions of T_reg cells in a mouse colitis model and in human cells isolated from the peripheral blood of healthy donors and patients with rheumatoid arthritis. Recruitment of PKC-θ to the immunological synapse is lower in T_reg cells than in effector cells because of sequestration of PKC-θ at the distal pole in T_reg cells. Treatment with tumor necrosis factor increases recruitment of PKC-θ to the immunological synapse and inhibits the suppressive abilities of T_reg cells, which correlates with previous observations of impaired T_reg cell function in rheumatoid arthritis. The mechanisms that control the recruitment of PKC-θ to the immunological synapse in effector T cells versus T_reg cells remain to be explored. IV

Science (25 March 2010) doi:10.1126/science.1186068

Helios marks nT _reg cells

Discriminating markers that distinguish T_reg cells that arise in the thymus (nT_regs cells) from those induced in the periphery are lacking at present. In the Journal of Immunology, Shevach and colleagues identify the Ikaros-family transcription factor Helios as being uniquely expressed in peripheral nT_reg cells. Helios expression occurs in double-negative thymocytes before Foxp3 expression, but it is abundant in CD4⁺CD25⁺CD44^hi cells. Only 70% of the peripheral Foxp3⁺ population in mice and are Helios⁺ while expression in humans is more variable. Although thymic Foxp3⁺CD4⁺ T cells express Helios, neither in vitro transforming growth factor-β nor in vivo oral tolerance regimens induce Helios expression in peripheral CD4⁺CD25⁻ cells, despite upregulation of Foxp3 expression. Intracellular cytokine staining shows that expression of IL-2, IL-17 and interferon-γ occurs only in the Helios-negative Foxp3⁺ population, which indicates the plasticity of iT_reg cells. Conditional loss of Helios does not alter thymic Foxp3 expression or nT_reg cell function. Conversely, scurfy mice, which lack Foxp3, express Helios. How nT_reg and iT_reg cells differ in their genomic signatures and whether Helios has a role in these differences in expression remains to be seen. LAD

J. Immunol. 184, 3433–3441 (2010)

Notch partners

The presence or absence of Notch, which influences cell fate, dictates whether the transcription factor RBP-J functions as an activator or repressor, respectively. In Genes & Development, Liefke et al. show that the histone demethylase KDM5A contributes to the tight temporal control of the expression of Notch target genes. Notch signaling induces permissive histone H3 Lys4 (H3K4) methylation of RBP-J regulatory sites. Inhibition of Notch signaling leads to a rapid demethylation of H3K4 marks associated with RBP-J and gene silencing, whereas intracellular Notch reestablishes H3K4 trimethylation at these sites. KDM5A directly interacts with RBP-J and can elute together with RBP-J during specific DNA affinity chromatography, which suggests that KDM5A is a corepressor. Overexpression of KDM5A suppresses Notch gene activation, whereas catalytic-site mutants fail to suppress this. Determining how intracellular Notch disrupts the RBP-J–KDM5A interaction will require further investigation. LAD

Genes Dev. 24, 590–601 (2010)

Written by Laurie A. Dempsey, Zoltan Fehervari & Ioana Visan