Lymphopenia-induced proliferation is a potent activator for CD4+ T cell-mediated autoimmune disease in the retina.

To study retinal immunity in a defined system, a CD4+ TCR transgenic mouse line (betagalTCR) specific for beta-galactosidase (betagal) was created and used with transgenic mice that expressed betagal in retinal photoreceptor cells (arrbetagal mice). Adoptive transfer of resting betagalTCR T cells, whether naive or Ag-experienced, into arrbetagal mice did not induce retinal autoimmune disease (experimental autoimmune uveoretinitis, EAU) and gave no evidence of Ag recognition. Generation of betagalTCR T cells in arrbetagal mice by use of bone marrow grafts, or double-transgenic mice, also gave no retinal disease or signs of Ag recognition. Arrbetagal mice were also resistant to EAU induction by adoptive transfer of in vitro-activated betagalTCR T cells, even though the T cells were pathogenic if the betagal was expressed elsewhere. In vitro manipulations to increase T cell pathogenicity before transfer did not result in EAU. The only strategy that induced a high frequency of severe EAU was transfer of naive, CD25-depleted, betagalTCR T cells into lymphopenic arrbetagal recipients, implicating regulatory T cells in the T cell inoculum, as well as in the recipients, in the resistance to EAU. Surprisingly, activation of the CD25-depleted betagalTCR T cells before transfer into the lymphopenic recipients reduced EAU. Taken together, the results suggest that endogenous regulatory mechanisms, as well as peripheral induction of regulatory T cells, play a role in the protection from EAU.