Retention of T cells within affected tissue is a critical component of adaptive immune inflammation. However, the mechanisms involved in T cell retention remain largely undefined. Previous studies revealed the capacity of cAMP signaling to regulate immune cell migration, as well as dynamic regulation of receptors that could induce cAMP production in immune cells. The potential for cAMP to act as a retention signal has been mostly unexplored, partially as a result of this second messenger's well-characterized inhibition of effector function in immune cells. Here, we report that cAMP regulates the tissue retention of mouse T cells at concentrations well below those that inhibited proliferation or decreased acquisition of an effector phenotype. Stimulation of CD4+ T cells with odorants known to be cognate ligands for T cell-expressed olfactory receptors induced cAMP and inhibited chemokine-driven chemotaxis without decreasing T cell proliferation or effector functions. Similar effects were observed following treatment with relatively low concentrations of the cAMP analog Sp-5,6-dichloro-1-β-d-ribofuranosylbenzimidazole-3',5'-monophosphorothioate. Furthermore, pretreatment with odorants or cAMP at concentrations that did not inhibit effector function induced T cell tissue retention in mice by inhibiting chemokine-dependent T cell egress from the footpad to the draining lymph node. Together, these results suggest that odorant receptor-mediated increases in intracellular cAMP can modulate T cell tissue trafficking and may offer new therapeutic targets for controlling T cell tissue accumulation.
Keywords: cell trafficking; extranasal; inflammation.
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