title: 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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Clark
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Saule
authors.initials: S
authors.lastname: Nurmukhambetova
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA; and.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Munger
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA jason.lees@usuhs.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Lees
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D020296:Animals, Congenic; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000637:transplantation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D006835:Hydrazones / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D037181:Lectins, C-Type / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009812:Odorants; D018035:Receptors, Odorant / Q000097:blood / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D005576:Colforsin; D000242:Cyclic AMP; D003998:Dicarboxylic Acids; D004004:Dichlororibofuranosylbenzimidazole; D005227:Fatty Acids; D006835:Hydrazones; D007555:Isoxazoles; D037181:Lectins, C-Type; D018035:Receptors, Odorant; D013873:Thionucleotides; D000099192:CD69 Antigens; C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; C071644:5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate; C008776:pelargonic acid; C010038:azelaic acid
keywords: cell trafficking; extranasal; inflammation