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 (beta gaITCR) specific for beta-galactosidase (beta gal) was created and used with transgenic mice that expressed beta gal in retinal photoreceptor cells (arr beta gal mice). Adoptive transfer of resting beta galTCR T cells, whether naive or Ag-experienced, into arr beta gal mice did not induce retinal autoimmune disease (experimental autoimmune uveoretinitis, EAU) and gave no evidence of Ag recognition. Generation of beta galTCR T cells in arr beta gal mice by use of bone marrow grafts, or double-transgenic mice, also gave no retinal disease or signs of Ag recognition. Arr beta gal mice were also resistant to EAU induction by adoptive transfer of in vitro-activated beta galTCR T cells, even though the T cells were pathogenic if the beta gal 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, beta galTCR T cells into lymphopenic arr beta gal 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 beta galTCR 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. The Journal of Immunology, 2009, 182: 969-979.