Homing in on leukotrienes

To mediate an effective immune response, T cells must find their way to sites of infection or inflammation. Changes in T-cell homing patterns following activation are thought to result from changes in the expression of homing molecules, including adhesion molecules and chemokine receptors, however, data now show that this might not be the whole picture. Three articles in the October issue of Nature Immunology report that leukotriene B₄ (LTB₄) — an arachidonic-acid-derived pro-inflammatory lipid — is also involved in T-cell recruitment.

Andrew Luster and colleagues, who generated mice deficient for the main LTB₄ receptor BLT1, showed that LTB₄ could direct the recruitment of CD4⁺ effector T cells. They showed that BLT1 was highly expressed by CD4⁺ effector T-cell subsets differentiated in vitro under T helper 1 (T_H1)- or T_H2-polarizing conditions and after activation in vivo. Expression of BLT1 enabled both subsets of CD4⁺ effector T cells to move by chemotaxis towards a LTB₄ gradient, whereas naive cells were unaffected by the presence of LTB₄. Both subsets of CD4⁺ effector T cells also adhered to endothelial cells under flow when exposed to LTB₄. They used their BLT1-deficient mice in an asthma model to show that the recruitment of early CD4⁺ and CD8⁺ T cells to the airways after aerosol challenge of previously immunized mice was dependent on the expression of BLT1.

An important source of LTB₄ was shown by Vanessa Ott et al. to be activated mast cells — the sentinel cells of the tissues' early warning system. They showed that activated mast cells could induce the migration of CD8⁺ effector T cells through the production of LTB₄. Therefore, LTB₄ seems to act as a link between the activation of innate immune cells and early recruitment of adaptive immune cells.

Ulrich von Andrian's group also investigated the response of CD8⁺ T-cell subsets to LTB₄. CD8⁺ naive, effector and central memory T cells have distinct migratory properties in vivo; naive and central memory T cells home to secondary lymphoid tissues, whereas effector T cells migrate efficiently to inflamed tissues. The authors showed that CD8⁺ effector T cells express high levels of BLT1, whereas CD8⁺ memory T cells express low levels. BLT1-expressing CD8⁺ effector T cells moved by chemotaxis towards LTB₄, whereas naive and memory cells did not. By contrast, LTB₄ induced the rapid accumulation of both effector and memory T cells, but not naive cells, in postcapillary venules by promoting the transition from rolling to firm arrest. This effect depended on signals mediated through BLT1, as cells from the BLT1-deficient mice did not arrest in response to LTB₄. Using a model of peritonitis, they showed that wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than BLT1-deficient effector cells, further indicating an important role for LTB₄–BLT1 interactions in the trafficking of CD8⁺ effector T cells in vivo.