CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance.
OBJECTIVE
The peripheral tolerance that arises after injection of antigen into the anterior chamber (anterior chamber-associated immune deviation; ACAID) is associated in part with CD8+ T cells that suppress the expression of Th1 and Th2 immunity. The purpose of these studies was to determine the genes and molecules that are critical for CD8+ T regulatory cell (T reg) functions in ACAID.


METHODS
Ovalbumin (OVA)-specific CD8+ T cells from T-cell receptor (TCR) transgenic OT-1 mice acquire efferent regulatory properties similar to in vivo-generated CD8+ T regs after stimulation with OVA-pulsed TGF-beta2-treated APCs. Changes in the genetic program associated with acquisition of efferent regulatory function in OT-1 CD8+ T cells in vitro were determined by DNA microarray analyses and confirmed by RT-PCR analyses and biological assays.


RESULTS
T regulatory OT-1 T cells acquired a novel transcriptional pattern indicative of their function. Genes for molecules associated with TGF-beta function, resistance to TCR-triggered apoptosis, and localization of cells to antigen deposition in peripheral tissues were upregulated, and genes related to cytolytic function were downregulated. Further study showed that CD103, a cell-adhesion molecule that binds E-cadherin, was highly upregulated in in vivo-generated ACAID T regs and was necessary for their suppression of T-cell activation in vitro.


CONCLUSIONS
OT-1 CD8 T cells modulated in vitro by exposure to antigen-pulsed, TGF-beta2-treated APCs expressed genes related to immune suppression. Thus, the necessity for CD103 emerges in the efferent CD8+ T-cell regulatory mechanisms in eye-derived tolerance.
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Hiroshi
H
Keino
Sharmila
S
Masli
Shuji
S
Sasaki
J Wayne
JW
Streilein
Joan
J
Stein-Streilein
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007109:Immunity; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053781:Transforming Growth Factor beta2; D015854:Up-Regulation
D015703:Antigens, CD; D039001:Integrin alpha Chains; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; C091367:alpha E integrins; D010047:Ovalbumin