Regulatory T cells: timing is everything

Comment on Setiady et al, page 1056

In this issue of Blood, Setiady and colleagues elegantly demonstrate that a rather short time of presentation of self antigen to regulatory T cells is sufficient to make them fully functional, which then results in prevention of autoimmunity.

Over the last years, accumulating data from several autoimmunity models suggested that CD25⁺ regulatory T cells can be triggered by exposure to low-level self antigens, thereby preventing autoimmunity. However, these findings were challenged by results from other models in which antigen exposure did not seem to have a major role in the induction of regulatory T cells.^1-3  Setiady and colleagues now provide strong evidence that the kinetics of self-antigen exposure are of great importance for the induction of regulatory T cells capable of preventing autoimmunity. Their data resolve major aspects of previously conflicting results from different autoimmune models.

To address the issue of self-antigen expression, Setiady and colleagues used 2 well-established models of autoimmunity, autoimmune prostatitis (EAP) and autoimmune ovarian disease (AOD). Early thymectomy (day 3 after birth) is necessary for both diseases to develop in mice. First, Setiady and colleagues addressed the role of regulatory T cells in the EAP model. Infusion of highly purified male regulatory T cells previously exposed to self antigens from the prostate within the donor were significantly more potent in suppressing EAP than regulatory T cells from female mice (see figure). When prostate development, and therefore prostate antigen expression, was suppressed in male donor mice, the suppressive capacity of the adoptively transferred regulatory T cells was comparable with regulatory T cells transferred from female mice. Restoration of prostate antigen expression in donor mice of regulatory T cells for only 6 days was sufficient to induce maximum suppressive function after transfer into EAP-prone recipient mice (see figure).

In striking contrast were results from the AOD model. Here, transfer of regulatory T cells from male or female mice was equally sufficient to suppress autoimmune disease. From these results, one might primarily conclude that self-antigen encounter is irrelevant for the suppressive effect of regulatory T cells in this model. On the contrary, the kinetics of antigen expression in the recipient mice indeed explained the discrepancy. In the AOD model, the self antigen is expressed beginning at birth, while in the EAP model, the self antigens are not expressed until 14 days after birth. Regulatory T cells transferred into AOD-prone mice on day 5 after birth immediately encounter self antigen and gain suppressive capacity in the recipient; therefore, the suppressive effect of the T cells is similar irrespective of origin. In the EAP model, however, regulatory T cells transferred from female mice do not encounter antigen for the next 9 days, while male regulatory T cells are already preprimed in the donor setting. It is the timing of antigen exposure that makes the difference. It is interesting to note that a period of lack of self-antigen expression apparently does not lower the suppressive capacity of donor regulatory T cells. The findings reported here by Setiady and colleagues are of critical value not only to better understand the immunobiology of regulatory T cells in autoimmunity and other diseases but also to better use this “window of opportunity” when developing therapeutic interventions targeting regulatory T cells. ▪