IL-2, Regulatory T Cells, and Tolerance

Abstract

IL-2 is a potent T cell growth factor that for many years was assumed to amplify lymphocyte responses in vivo. Accordingly, IL-2 has been used clinically to enhance T cell immunity in patients with AIDS or cancer, and blocking Abs to the IL-2R are used to inhibit T cell responses against transplanted tissues. It was later shown in mice that, unexpectedly, disruption of the IL-2 pathway results in lymphoid hyperplasia and autoimmunity rather than immune deficiency, indicating that the major physiological function of IL-2 is to limit rather than enhance T cell responses. This apparent paradox has recently been resolved with the discovery that IL-2 is critical for the development and peripheral expansion of CD4+CD25+ regulatory T cells, which promote self-tolerance by suppressing T cell responses in vivo. Our new understanding of IL-2 biology prompts a re-evaluation of how best to clinically manipulate this important immunoregulatory pathway.

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…Despite the functional significance of CD25 and IL-2 signalling in naturally occurring Treg [11][12][13][14][15][16], the data presented here document deletion of diabetogenic cells by the fusion protein. Targeting cells that express the IL-2 receptor decreased the responsiveness to alloantigens in vitro, impaired adoptive transfer of the disease into NOD SCID mice and antagonised cyclophosphamide-induced destructive insulitis.…”

“…IL-2 is an attractive target of immunotherapy as an important constituent of immune activation [9,10]. Subsets of naturally occurring Treg that emerge from the thymus as a distinct cell type [11,12] are not only characterised by expression of high levels of the high-affinity α chain of the IL-2 receptor (CD25) [13], but also depend on IL-2 for their expansion and function [14,15]. The implications and pleiotropic functions of IL-2 in autoimmune disorders have been extensively debated.…”

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

“…Secondly, the optimal method of expanding T cells for transduction is still being debated. We routinely use IL-2 to expand T cells, but evidence is emerging that this may also assist in the expansion of regulatory T cells, this subpopulation may be impeding some of the observed cytotoxicity that we are engineering in to these cells (Nelson, 2004). There may be advantages in using different cytokines such as IL-7 and IL-15 to grow cytotoxic T cells (Antony and Restifo, 2005), or alternatively magnetically depleting regulatory cells from the precursor population.…”

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

“…Both IL-2-and IL-2R-deficient mice are prone to develop autoimmunity and may develop lymphoproliferative diseases [12][13][14][15][16][17]. Thus, IL-2 is implicated in promoting as well as inhibiting T cell responses [18].…”