title: An aberrant thymus in CCR5-/- mice is coupled with an enhanced adaptive immune response in fungal infection.
abstract: CCR5 is a potent mediator of regulatory T cell (Treg) chemotaxis. In murine histoplasmosis, mice lacking CCR5 or endogenous CCL4 have a reduced number of Tregs in the lungs, which results in accelerated resolution of infection. In this study, we demonstrate that CCR5 controls the outcome of Histoplasma capsulatum infection by dictating thymic and lymph node egress of Tregs. Mice lacking CCR5 or treated with a mAb to CCL4 had more Tregs in the thymus prior to and during infection. Thymic accumulation was associated with diminished transcription of the sphingosine 1-phosphate 1 receptor and Krüppel-like factor 2, both of which regulate thymic and lymph node emigration of T cells. The significance of CCR5 in Treg egress was demonstrated by generating mixed bone marrow chimeras. Chimeric mice had an increased proportion of CCR5(-/-) Tregs in the thymus and lymph nodes and a decreased proportion of Tregs in the lungs prior to and during H. capsulatum infection. Hence, CCR5 signaling regulates pathogen persistence in murine histoplasmosis by regulating Tregs exiting from the thymus and lymph nodes and, consequently, their subsequent homing in the periphery.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Kroetz
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002465:Cell Movement; D054407:Chemokine CCL4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D006658:Histoplasma / Q000276:immunology; D006660:Histoplasmosis / Q000276:immunology* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008168:Lung / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011828:Radiation Chimera; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D049349:Receptors, Lysosphingolipid / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D054407:Chemokine CCL4; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D019713:Receptors, CCR5; D049349:Receptors, Lysosphingolipid