Generating and Sustaining Stable Autoantigen-specific CD4 and CD8 Regulatory T Cells in Lupus

Recently, several worldwide clinical and pre-clinical trials have demonstrated a significant benefit of low dose IL-2 mediated Treg cell increase in multiple autoimmune diseases, including lupus. This result is of special interest in lupus because it has been known for decades that during lupus the immune system has a relative deficiency of IL-2 production that results in a decrease in regulatory T cells and a simultaneous increase in T follicular helper (Tfh) cells. Thus, the low dose IL-2 therapy benefits lupus in several ways, but the effect is very short-lived, as the level of Treg comes down rapidly. Moreover, the Tregs generated by the therapy are non-specific and probably unstable, meaning that they could convert to pathogenic T cells in the inflammatory environment of lupus. The reason for this dilemma is that continuous T cell receptor signals are required to maintain a functional regulatory T cell pool, and effector Tregs are very potent only after rounds of antigen specific activation in low intensity. Therefore, autoantigen-derived peptide epitopes for T cells of lupus that have been proven to be tolerance-inducing in low-doses because they generate autoantigen-specific CD4 and CD8 regulatory T cells, are crucial for generating and sustaining stable Treg. Moreover, the subset of regulatory CD8 T cells induced by some of the peptide epitopes are especially beneficial in human lupus. The autoantigen peptide epitopes, however, may require special delivery system involving nanoparticles and adjunct therapy with anti-inflammatory agents to secure their durable tolerogenicity in lupus patient. Thus, this Research Topic invites contributions from experts related to, but not limited to, the following categories:

1) Lupus T cell epitopes with known Treg inducing ability/tolerogenicity;
2) Tolerogenic delivery of epitopes, such as in nanoparticles;
3) Treg stability maintenance mechanisms, such as molecular and epigenetic mechanisms, metabolic mechanisms;
4) Potentiate peptide tolerance by IL-2 and other adjunct therapy such as IL-2 in low dose, or in nanoparticles, IL-2 muteins, or pegylated IL-2, and other agents.

David Horwitz has co-founded Toralgen, INC and General Nanotherapeutics, LLC but is receiving no compensation for either company. All other Topic Editors declare no conflicts of interest related to the topic theme