title: T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression.
abstract: T regulatory cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and nonharmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require these cells to be near their targets of suppression; however, it is not known how Treg-to-target proximity is controlled. Here, we found that Tregs attract CD4+ and CD8+ T cells by producing chemokines. Specifically, Tregs produced both CCL3 and CCL4 in response to stimulation, and production of these chemokines was critical for migration of target T cells, as Tregs from Ccl3-/- mice, which are also deficient for CCL4 production, did not promote migration. Moreover, CCR5 expression by target T cells was required for migration of these cells to supernatants conditioned by Tregs. Tregs deficient for expression of CCL3 and CCL4 were impaired in their ability to suppress experimental autoimmune encephalomyelitis or islet allograft rejection in murine models. Moreover, Tregs from subjects with established type 1 diabetes were impaired in their ability to produce CCL3 and CCL4. Together, these results demonstrate a previously unappreciated facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their therapeutic effect in autoimmunity and transplantation.
authors: Scott J
authors: SJ
authors: Patterson
authors: Anne M
authors: AM
authors: Pesenacker
authors: Adele Y
authors: AY
authors: Wang
authors: Jana
authors: J
authors: Gillies
authors: Majid
authors: M
authors: Mojibian
authors: Kim
authors: K
authors: Morishita
authors: Rusung
authors: R
authors: Tan
authors: Timothy J
authors: TJ
authors: Kieffer
authors: C Bruce
authors: CB
authors: Verchere
authors: Constadina
authors: C
authors: Panagiotopoulos
authors: Megan K
authors: MK
authors: Levings
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis* / Q000378:metabolism; D054407:Chemokine CCL4 / Q000096:biosynthesis* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D002648:Child; D002675:Child, Preschool; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019713:Receptors, CCR5 / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C515429:CCL3 protein, human; C066507:CCL4 protein, human; C000592874:CCR5 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019713:Receptors, CCR5