IMMUNOBIOLOGY LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function

Despite encouraging results using lym-phocyte function antigen-1 (LFA-1) block-ade to inhibit BM and solid organ trans-plantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allo-geneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti–LFA-1–treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62LloCD44hi profile. We determined that this change was due to a specific enrich-ment of activated, graft-specific effectors in the peripheral lymph nodes of anti– LFA-1–treated mice compared with un-treated controls, and not to a direct effect of anti–LFA-1 on CD62L expression. LFA-1 blockade also resulted in a dramatic in-crease in the frequency of CD4 FoxP3 regulatory T cells in graft-draining nodes. Our results suggest that the differential impact of LFA-1 blockade on the distribu-tion of naive versus effector and regula-tory T cells may underlie its ability to inhibit alloreactive T-cell responses after transplantation. (Blood. 2011;118(22): 5851-5861