IL-16 Mediates CD4 T Lymphocyte Accumulation in the lymph nodes by desensitizing S1P1 (134.1)

Abstract

Abstract IL-16 is a cytokine generated at sites of inflammation. Originally characterized as a CD4 ligand that induces migration, it is now known that IL-16 can alter TCR-induced cell activation and inhibit many chemokine receptors via cross-receptor desensitization. Previous work has demonstrated that stimulation by HIV-1 gp120 results in greater CCL21 induced migration with concomitant inhibition of sphingosine-1-phosphate (S1P) induced migration. Injection of gp120 into SCIDhu mice resulted in sequestration of CD4+ T cells within lymph nodes. We now investigated whether a natural ligand for CD4, IL-16, could similarly affect T cell homing. We found that IL-16 could not augment CCL21; however, was capable of inhibiting S1P induced migration. This effect was dependent on p56lck signaling and did not affect S1P receptor expression. IL-16 intratracheal instillation resulted in initial recruitment of CD4+ cells into the lung with subsequent recruitment into lung draining lymph nodes. Instillation of eotaxin-2 resulted in lung accumulation but not lymph node accumulation of T cells. The effect by IL-16 was CD4 dependent as no accumulation was seen using CD4-/- mice. Accumulation within the nodes occurred 2 h post instillation and resolved by 24 h. We propose that this is the first description of cytokine desensitization of S1P stimulation and further, suggests an additional mechanism by which IL-16 can regulate recruitment of cells and mediate the inflammatory process.