Abstract
Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.
Highlights
During this phase of in vivo T cell reconstitution, expansion of Tregs can be favored by the administration of IL-2/anti-IL-2 immune complexes that, combined with agonist signaling through tumor necrosis factor receptor (TNFR), provides an advantage to Tregs over alloreactive T cells and tips the balance towards regulation instead of aggressive response
Etanercept (TNF decoy receptor) and infliximab are two examples of the most common Tumor Necrosis Factor (TNF) blockers approved for clinical use as a second line for the treatment of steroid-refractory graft-versus-host disease (GvHD) and autoimmune diseases either alone or in combination with methotrexate; some patients do not respond, and disease can be exacerbated upon TNF blockade
This undesirable outcome may be the result of inhibition of Tregs suppressive function that prevents membrane-bound TNF binding to TNFR2
Summary
The initial description of T cells exhibiting suppressive function is attributed to Nishizuka and coworkers. The initial, spontaneous, fast peripheral T cell expansion due to active proliferation in response to lymphopenia takes advantage of the presence of an abundant amount of freely available cytokines in the internal milieu and plenty of antigen-driven signals This abnormal proliferation needs to be regulated at early time points to control the undesirable side effects of a newly generated oligoclonal T cell repertoire mainly composed of effector/memory T cells resistant to immunosuppression in the recipient of an allograft [28,41]. Thymic emigration is paramount to regulate the rate of recovery of the peripheral T cell pool through a process termed lymphopenia-induced slow proliferation During this phase of in vivo T cell reconstitution, expansion of Tregs can be favored by the administration of IL-2/anti-IL-2 immune complexes that, combined with agonist signaling through TNFR, provides an advantage to Tregs over alloreactive T cells and tips the balance towards regulation instead of aggressive response. This idea places Tregs at the central stage of current research
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