Odorants specifically modulate chemotaxis and tissue retention of CD4+ T cells via cyclic adenosine monophosphate induction

Abstract

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.

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

“…The concentration of cAMP produced is an important factor that has, as yet, not been taken into sufficient account. The dependence of cellular functions on the concentration of cAMPelevating agents has been studied recently by Clark et al [180] in T cells. They show that stimulation through the odorant GPCRs or low concentrations of cAMP analogs results in the selective unresponsiveness of T cells to chemokine receptors, such as CCR7, which helps in the egress of T lymphocytes from nonlymphoid tissues (e.g., lung and skin) [181,182].…”

Potential depression and antidepressant-response biomarkers in human lymphoblast cell lines from treatment-responsive and treatment-resistant subjects: roles of SSRIs and omega-3 polyunsaturated fatty acids

“…3). Normally, G olf α is highly expressed in olfactory neurons where it is coupled with odorant receptors (ORs), although it is found in both the frontal cortex and lymphocytes [72]. One role for G olf α is to activate AC3, and this is the second most abundant adenylyl cyclase in LCLs.…”

The Intestinal Fatty Acid-Enteroendocrine Interplay, Emerging Roles for Olfactory Signaling and Serotonin Conjugates

“…An abundant number of gene transcripts for class I odorant receptors, the most ancient class of ORs conserved throughout evolution, were found to be expressed on five different types of human blood leukocytes, including bone-marrow-derived lymphocytes (B cells) and T cells [ 7 ]. Functional relevance for ORs has been shown for CD4+ T cells, of which trafficking abilities were largely diminished by odorant stimulation [ 17 ]. In addition, in lung macrophages, odorants enhanced both OR expression, monocyte chemoattractant protein-1 (MCP-1) production and macrophage migration, but only in the presence of inflammatory triggers [ 18 ].…”

“…Meanwhile, it has become clear that functional ORs are expressed in many non-olfactory tissues including testis, prostate, kidney, adipose tissue, muscle, skin, hair, immune cells, heart, pancreas [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], and the GI tract [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Here, they play a role in diverse physiological processes varying from sperm chemotaxis, modulation of cancer cell proliferation, blood pressure regulation and immune cell migration to adiposity, gut hormone release, and modulation of energy- and insulin metabolism [ 3 , 5 , 9 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Throughout the body they act as chemosensors for endogenous molecules that have only partly been identified thus far.…”