Tolerogenic dendritic cells induced by withdrawal of polyunsaturated fatty acid DHA and mTOR inhibitor PP242 attenuate allograft rejection

Dendritic cells (DCs) exhibit the capacity to elicit either immune activation or tolerance, contingent upon diverse induction conditions. However, the crucial factors governing the induction of tolerogenic dendritic cells (Tol-DCs) remain obscure. Our study demonstrates that the combined use of docosahexaenoic acid (DHA) and the mammalian target of rapamycin inhibitor PP242 (comb-DHA) markedly hinders DC maturation while maintaining DC phagocytic capabilities in an immature state, thereby enabling substantial and sustained DHA accumulation within cells. Upon withdrawal of exogenous drug intervention, we observe that the retained DHA within the DCs facilitates delayed activation of p-AKT ^Ser473 and PTDSS2-related pathways, ultimately leading to the induction of a novel type of Tol-DC, comb-DHA-DC. These Tol-DCs display significantly reduced expression of costimulatory molecules and possess the ability to profoundly inhibit T-cell proliferation. Adoptive transfer of comb-DHA-DCs suppresses allograft rejection reactions. In summary, our findings reveal a novel strategy for inducing Tol-DCs and present a promising therapeutic avenue for enhancing graft tolerance.