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1 From the Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
PURPOSE. To determine by what mechanism(s) iris and ciliary body (I/CB) pigment epithelial (PE) cells inhibit T-cell activation in vitro.
METHODS. Pure cultured I/CB PE cells were obtained from eyes of normal and CD95
ligand (CD95L)-deficient mice and tested for their capacity to suppress
T-cell activation in three different T-cell receptor (Tcr) ligand
systems: mixed lymphocyte reactions, stimulation of Tcr transgenic T
cells (D011.10) by specific antigen (ovalbumin), and ligation of the
Tcr-associated CD3 molecule by anti-CD3 antibodies. Proliferation and
secretion of cytokines (interferon [IFN]-
, interleukin [IL]-2,
IL-4, and IL-10) were assessed as measures of T-cell activation.
Suppressive influences of I/CB PE cells were determined on the basis of
RT-PCR–detected cytokine genes expressed by I/CB PE cells,
immunosuppression mediated by supernatants of cultured I/CB PE cells,
direct contact between I/CB PE cells and T lymphocytes, and promotion
of apoptosis among responding T cells. Attempts to reverse I/CB
PE–dependent suppression of T-cell activation included the use of
neutralizing antibodies to IL-10, tumor necrosis factor (TNF)-
and
transforming growth factor (TGF)-ß, and the addition of exogenous
IL-2 and IL-12.
RESULTS. Cultured mouse I/CB PE cells (including CD95L-deficient cells), which
were more than 95% keratin positive, suppressed T-cell proliferation
and secretion of IFN-, IL-2, IL-4, and IL-10 in a dose-dependent
fashion in all three Tcr ligand systems. Supernatants of cultured I/CB
PE cells displayed little suppression activity, whereas cultures in
which I/CB PE cells contacted responding T cells directly were
profoundly immunosuppressive. Cultured I/CB PE cells expressed mRNA for
TGF-ß1, TGF-ß2, IL-6, IL-10, and TNF-, but not IL-4, IFN-,
proopiomelanocortin (POMC), and CD95L (Fas L). Antibodies to
TGF-ß, IL-10, and TNF- failed to reverse suppression mediated by
I/CB PE cells. Moreover, neither exogenous IL-2 or IL-12 relieved the
suppression.
CONCLUSIONS. Cultured I/CB PE cells, through direct cell-to-cell contact, prevent T cells from proliferating and secreting cytokines when stimulated through the Tcr for antigen by a mechanism that does not involve CD95 or apoptosis.
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