The ability to trap lymphocytes within lymph nodes or to allow their recirculation is an important feature of mounting an effective adaptive immune response. In a typical antigen-specific response to

infection, local inflammation triggers activation and retention of cells in the relevant draining lymph node, and this accumulation increases the probability of lymphocytes finding cognate antigens and becoming activated. This is believed to occur in three phases, the first of which is the initiation of short serial contacts between T cells and antigen-bearing dendritic cells allowing selleck products T cells that are specific for dendritic cell-presented antigen to up-regulate activation markers and decrease their

motility.[21] Approximately 12 hr later, stable contacts are formed between dendritic cells and T cells, which begin to produce effector cytokines. In the last phase, T cells become primed for migration and have developed pronounced effector functions. Shiow et al. observed that T-cell and B-cell numbers precipitously decrease in the circulating lymph[22] after treating mice with poly I:C, which mimics viral double-stranded RNA and is therefore a potent inducer of interferon-α/β production. This lymphopenia was attributable to a decrease in lymphocyte S1P1 responsiveness to S1P and therefore decreased egress. The interferon GW572016 response also led to surface expression of the activation marker CD69, which was required for lymphocyte retention, as Cd69−/− cells transferred to wild-type hosts were refractory to the induction of lymphopenia by poly I:C injection or infection with lymphocytic choriomeningitis virus. In vitro studies later demonstrated that an interaction between specific domains of CD69 and S1P1 was required for their reciprocal regulation

and mutual exclusion from expression on the cell surface.[23] find more A model was proposed whereby S1P1 expression prevents CD69 surface expression, allowing unactivated lymphocytes to exit lymphoid organs. Alternatively, cellular activation promotes lymphocyte retention by up-regulating surface expression of CD69, so forcibly reducing S1P1 surface expression and S1P responsiveness. The balance between C-C chemokine receptor type 7 (CCR7) retention signals and S1P1 egress signals is also important for modulating T-cell activation.[24, 25] CCR7 is a chemokine receptor for the T-cell cortex homing chemokines C-C motif ligand 19 (CCL19) and CCL21.[26] Exposure to high concentrations of S1P results in S1P1 internalization, making cells unresponsive to migration cues in blood or lymph,[20, 27] whereas CCL19 can desensitize CCR7 signalling.[28] Loss of CCR7 results in reduced T-lymphocyte dwell time in the lymph node, implying that CCR7 provides a signal to counter S1P1-mediated egress.