It is generally thought that interferon-γ (IFNγ) and interleukin-4 (IL-4) (the canonical T helper 1 (TH1)-type and TH2-type cytokines, respectively) function locally and only activate those cells that are in close proximity to the cytokine source. Perona-Wright et al. have challenged this view by showing that IFNγ and IL-4 signal to most lympho cytes in the reactive lymph node. Furthermore, bystander con-ditioning of naive T cells by IL-4 can inhibit their subsequent polarization to a TH1 cell phenotype.

The authors began their study by examining IL-4-induced signalling in the reactive lymph nodes of mice infected with the TH2 cell-inducing enteric helminth Heligmosomoides polygyrus. Previous study of helminth infec-tions had suggested that IL-4-induced signalling may be highly restricted to follicular lymphocyte populations. However, follow-ing infection with H. polygyrus, phospho rylated signal transducer and activator of transcription 6 (STAT6) could be detected in almost all B and T cells throughout the draining mesenteric lymph nodes. No STAT6 phosphorylation was observed in lymphocytes from infected IL-4-deficient or IL-4

receptor-α-deficient mice, indicating that lymphocyte expression of phos-phorylated STAT6 was a specific indicator of IL-4-induced activation.

To determine whether similar widespread IFNγ signalling also occurred during a TH1-type response, the authors infected mice orally with the TH1 cell-inducing intra cellular parasite Toxoplasma gondii and examined phosphorylation of STAT1. Most lymphocytes from the draining lymph nodes of T. gondii-infected mice contained phosphorylated STAT1 and surface-bound IFNγ — indicating that IFNγ, like IL-4, can signal throughout the entire lymph node. By contrast, the actions of the TH1 cell-polarizing cytokine IL-12 were found to be tightly restricted following T. gondii infection, with only a small number of T cells in the draining lymph nodes showing evi-dence of IL-12-induced signalling.

Next, the authors used IL-4 reporter mice to assess whether IL-4-induced signalling extends beyond the reactive lymph node. They found that IL-4 production occurred only in lymph nodes draining sites of H. polygyrus challenge and, although IL-4-induced signalling was wide-spread throughout the draining node, the actions of this cytokine did not spread to non-draining lymph nodes or the spleen. Strikingly, however, STAT6 phosphory lation was sustained for weeks in T cells in reactive lymph nodes; experiments with specific neutral izing anti-bodies showed that this was due to continuous IL-4-induced signalling.

Cy to k i n e s

Cytokines reach out

Finally, the authors addressed

whether bystander conditioning of naive

T cells in reactive lymph nodes could affect their subsequent responses to cognate antigen. Mice were adoptively transferred with naive ovalbumin (OVA)-specific CD4+ T cells and then challenged in the footpad with TH1 cell-polarizing dendritic cells (DCs) (generated by pulsing DCs with OVA peptide and heat-killed Yersinia pestis). When H. polygyrus larvae were injected into the footpad to induce a TH2 cell-dominant environment prior to challenge with the TH1 cell-polarizing DCs, subsequently isolated OVA-specific T cells produced less IFNγ and higher levels of IL-4 in response to OVA peptide ex vivo. This indi-cated that bystander conditioning in the reactive lymph node during a TH2-type response could override subsequent TH1 cell polarization. These findings suggest that T cell polarization can be affected by helminths in a non-specific manner and, as such, have important implica-tions for vaccine design in areas of endemic parasitic infection.

Yvonne Bordon

oRiGinAL ReseARCH PAPeR Perona-Wright, G. et al. Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nature Immunol. 25 Apr 2010 (doi:10.1073/ni.1866)

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NATure reVIeWS | Immunology VOLuMe 10 | juNe 2010

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