A breathtaking chemokine

Allergic asthma is a chronic inflammatory lung disease that is thought to be driven by T helper 2 (T_H2) cells, but our understanding of the mechanisms responsible for T cell recruitment and activation in the allergic lung remains limited. A new study in Nature Medicine now shows that CX₃C-chemokine receptor 1 (CX₃CR1) and its ligand, CX₃C-chemokine ligand 1 (CX₃CL1), exacerbate allergic airway disease by promoting the survival of effector T cells in the inflamed lung.

Previous studies showed that the expression of CX₃CL1 increases in asthmatic lungs following allergen exposure; therefore, the authors explored the functions of the CX₃CL1–CX₃CR1 axis during allergic airway inflammation in mice. They found that in various models of allergic airway inflammation, CX₃CR1-deficient mice developed less severe airway disease than wild-type controls. This was characterized by reduced airway hyperreactivity and mucus secretion, fewer inflammatory lung infiltrates and lower levels of T_H2-type cytokines. Wild-type mice treated with CX₃CR1-blocking antibodies or the CX₃CL1 antagonist FKN-AT before allergen challenge also developed less severe airway disease. Importantly, intranasal administration of FKN-AT was also effective therapeutically in mice with pre-established airway inflammation.

The authors showed that few T cells from naive mice expressed CX₃CR1, but up to one-third of T_H2 cells in the inflamed airways expressed this chemokine receptor. CD4⁺ T cells purified from draining lymph nodes of allergen-sensitized CX₃CR1-deficient mice produced similar levels of T_H2-type cytokines to those from wild-type mice. However, only transfer of wild-type CD4⁺ T cells and not CX₃CR1-deficient T cells could restore airway inflammation to wild-type levels in CX₃CR1-deficient mice. Furthermore, if wild-type allergen-specific T_H2 cells were treated with FKN-AT before transfer, they could no longer promote increased airway inflammation in CX₃CR1-deficient mice.

Competition assays revealed that CX₃CR1 was not necessary for the differentiation of T_H2 cells or for their recruitment to the inflamed lung following allergen challenge. However, compared with wild-type T cells, CX₃CR1-deficient T cells showed increased rates of apoptosis in the inflamed lung, and in vitro, CX₃CL1 was shown to promote the survival of wild-type but not CX₃CR1-deficient T_H2 cells. Expression of CX₃CR1 also increased the survival of allergen-specific T_H1 cells that were transferred to the inflamed lung, but CX₃CR1 did not increase T_H2 cell survival in resting or inflamed popliteal lymph nodes.

Finally, the authors showed that CX₃CR1-deficient T cells that were transfected with the anti-apoptotic protein B cell lymphoma 2 (BCL-2) were maintained in inflamed lungs at similar frequencies to wild-type cells. Furthermore, BCL-2-transfected CX₃CR1-deficient T_H2 cells could promote airway inflammation in CX₃CR1-deficient mice as effectively as wild-type T_H2 cells. These data highlight a previously unappreciated role for the CX₃CL1–CX₃CR1 axis in promoting allergic airway inflammation; the authors suggest that intranasal delivery of CX₃CL1 antagonists could be an effective new therapy for patients with corticosteroid-resistant asthma.