Tolerance Promoting Therapies Result in Early Restraint of T Cell Reactivity rather than Conversion to a Regulatory Phenotype

CD8[sup +] T cells are primary mediators of acute islet allograft rejection and thus are potentially key targets of tolerance-inducing therapies. While monoclonal antibody therapy targeting LFA-1 (adhesion) or CD154 (costimulation) can independently induce allograft tolerance, their respective impact on graft-reactive CD8[sup +] T cells has remained unclear. Therefore, we determined the impact of anti-LFA-1 or anti-CD154 therapy on the fate of antigen-specific CD8[sup +] T cells and islet allograft survival in vivo. LFA-1 and CD154 directed therapies inhibit but do not intrinsically tolerize antigen-specific T cells or directly convert such cells to a regulatory phenotype. Rather, active regulatory tolerance appears to develop over time. As such, this early 'metastable' phase of tolerance (< 3 wks) is especially vulnerable to disruption to immune insults, such as with pathogen-associated innate stimulatory signals.