title: Functional Foxp3+ CD4+ CD25(Bright+) "natural" regulatory T cells are abundant in rabbit conjunctiva and suppress virus-specific CD4+ and CD8+ effector T cells during ocular herpes infection.
abstract: We studied the phenotype and distribution of "naturally" occurring CD4(+) CD25(+) T regulatory cells (CD4(+) CD25(+) nT(reg) cells) resident in rabbit conjunctiva, the main T-cell inductive site of the ocular mucosal immune system, and we investigated their suppressive capacities using herpes simplex virus type 1 (HSV-1)-specific effector T (T(eff)) cells induced during ocular infection. The expression of CD4, CD25, CTLA4, GITR, and Foxp3 was examined by reverse transcription-PCR, Western blotting, and fluorescence-activated cell sorter analysis in CD45(+) pan-leukocytes isolated from conjunctiva, spleen, and peripheral blood monocyte cells (PBMC) of HSV-1-infected and uninfected rabbits. Normal conjunctiva showed a higher frequency of CD4(+) CD25((Bright+)) T cells than did spleen and PBMC. These cells expressed high levels of Foxp3, GITR, and CTLA4 molecules. CD4(+) CD25((Bright+)) T cells were localized continuously along the upper and lower palpebral and bulbar conjunctiva, throughout the epithelium and substantia propria. Conjunctiva-derived CD4(+) CD25((Bright+)) T cells, but not CD4(+) CD25((low)) T cells, efficiently suppressed HSV-specific CD4(+) and CD8(+) T(eff) cells. The CD4(+) CD25((Bright+)) T-cell-mediated suppression was effective on both peripheral blood and conjunctiva infiltrating T(eff) cells and was cell-cell contact dependent but independent of interleukin-10 and transforming growth factor beta. Interestingly, during an ocular herpes infection, there was a selective increase in the frequency and suppressive capacity of Foxp3(+) CD4(+) CD25((Bright+)) T cells in conjunctiva but not in the spleen or in peripheral blood. Altogether, these results provide the first evidence that functional Foxp3(+) CD4(+) CD25((Bright+)) T(reg) cells accumulate in the conjunctiva. It remains to be determined whether conjunctiva CD4(+) CD25(+) nT(reg) cells affect the topical/mucosal delivery of subunit vaccines that stimulate the ocular mucosal immune system.
authors.affiliation: Cellular and Molecular Immunology Laboratory, The Eye Institute, University of California, Irvine, CA 92697-4375, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.forename: Gargi
authors.initials: G
authors.lastname: Dasgupta
authors.forename: Alami Aziz
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Sylvaine
authors.initials: S
authors.lastname: You
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Morishige
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wahlert
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Brown
authors.forename: James V
authors.initials: JV
authors.lastname: Jester
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wechsler
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003228:Conjunctiva / Q000166:cytology* / Q000276:immunology; D005260:Female; D018928:Immunity, Mucosal; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D016849:Keratitis, Herpetic / Q000276:immunology*; D011817:Rabbits
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit