Chemokines: The new co-stimulators of T cells

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Chemokine receptor signaling at the immunological synapse enhances T cell activation by strengthening T cell and antigen-presenting cell conjugation.

Ligand-occupied chemokine receptors classically induce G-protein mediated signaling pathways, resulting in cell migration and the stimulation of integrin-dependent adhesion. Viola et al. now propose a new function for chemokines; that of costimulatory molecules involved in the functioning of the immunological synapse.

By using T cells expressing fluorescently-tagged chemokine receptors, the authors showed that CCR5 and CXCR4 receptors were recruited to the immunological synapses formed between T-cells and infected antigen-presenting cells (APCs). Recruitment of chemokine receptors was dependent upon the formation of a productive synapse — involving activation of T cell receptor signaling — and on the interaction of the chemokine receptor with ligands secreted by the APC. Clustering of chemokine receptors was abolished when APC cells were treated with a drug that blocks protein secretion or when the T cells were treated with chemokine receptor antagonists.

Furthermore, chemokine receptors clustered at the immunological synapse coupled to G_q and/or G₁₁ protein signaling but were independent of G_isignaling; a coupling event indicative of preferential chemokine-induced adhesiveness rather than cell chemotaxis. The authors therefore favored the hypothesis that chemokine receptor recruitment to the immunological synapses reduces the responsiveness of the T cell to other chemoattractants, thus avoiding T cell ‘distraction’ and reinforcing T cell–APC attraction. Indeed, T cell–APC conjugates exposed to a chemokine gradient were more readily dismantled when protein secretion was inhibited, suggesting that one of the factors reinforcing T cell–APC attraction could be the release of chemokines into the synaptic cleft.

Furthermore, T cell production of superantigen-induced interferon- gamma was significantly reduced when protein secretion was blocked in APCs. In contrast, interferon- gamma production and proliferation by T cells was enhanced when the cells were challenged with chemokine agonists immobilised on beads coated with antibody to CD3. These results suggest that chemokine receptors enhance T cell activation by acting as costimulatory molecules.

The idea of chemokine involvement in the duration of the T cell–APC interaction is not new. However, these findings by Viola et al. are the first attempt to demonstrate the direct involvement of soluble molecules, such as chemokines, in the functioning of an immunological synapse. If these findings hold up under stricter physiological conditions, chemokines may be viewed in the future as the immunological equivalent of neurotransmitters.

Myrto Raftopoulou
Signaling Gateway

References

Molon, Barbara, Gri, Giorgia, Bettella, Monica, Gómez-Moutón, Concepción, Lanzavecchia, Antonio, Martínez, Carlos, Mañes, Santos, & Viola, Antonella. T cell costimulation by chemokine receptors. Nature Immunology 6, 465–471 (2005); ni1191 | Article | PubMed |
Trautmann, Alain. Chemokines as immunotransmitters?. Nature Immunology 6, 427–428 (2005); ni0505-427 | Article | PubMed |