Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function

Abstract

Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its impact on both regulatory T (Treg) and effector T (Teff) cells. However, the precise role of IL-2 in the maintenance and function of Treg cells in the adult peripheral immune system remains unclear.Here, we report that neutralization of IL-2 abrogated all IL-2 receptor signaling in Treg cells, resulting in rapid dendritic cell (DC) activation and subsequent Teff cell proliferation. By contrast, despite substantially reduced IL-2 sensitivity, Treg cells maintained selective IL-2 signaling and prevented immune dysregulation following treatment with the inhibitory anti-CD25 antibody PC61, even when CD25 hi Treg cells were depleted. Thus, even with severely curtailed CD25 expression and function, Treg cells maintain selective access to IL-2 in vivo. Antibody-mediated targeting of CD25 is being actively pursued for treatment of autoimmune disease and preventing allograft rejection, and our findings help inform therapeutic manipulation and design for optimal patient outcomes. Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its role in the development, maintenance and function of T regulatory (Treg) cells and its impact on effector cell proliferation and differentiation [1,2]. The IL-2 receptor can be composed of 2 or 3 subunits: IL-2Rβ (CD122) and the common gamma (γc) chain (CD132) together form the intermediate affinity receptor, and the addition of IL-2Rα (CD25) creates the high affinity receptor. Binding of CD25 to IL-2 induces a conformational change that decreases the energy needed to bind to the rest of the receptor, whereas CD122 and CD132 are the critical signaling chains [3]. Treg cells constitutively express CD25, which under homeostatic conditions allows them to outcompete CD25 -T effector (Teff) cells and natural killer (NK) cells for limiting amounts of IL-2. This is most important in the secondary lymphoid organs (SLOs), where prosurvival signals downstream of IL-2 signaling maintain Treg cells [4,5]. Notably, Treg cells cannot make their own IL-2 [6, 7] and depend on IL-2 produced mainly from autoreactive CD4 + Teff cells [8,9]. In this way, Teff and Treg cell populations are dynamically linked and reciprocally control each other to maintain immune homeostasis [10].When the IL-2-dependent balance of Treg and Teff cells is disrupted, autoimmunity and inflammation can occur. Genetic deficiency in CD25, CD122, or IL-2 results in systemic autoimmune disease in mice [11], and single nucleotide polymorphisms (SNPs) in the IL2 and IL2RA genes are associated with multiple autoimmune diseases in both mice and humans [12,13]. Therefore, manipulating the IL-2 signaling pathway therapeutically for treatment of autoimmune disease is an area of immense interest. Low dose IL-2 therapy, which enriches Treg cells, has shown efficacy in a wide variety of murine autoimmune models [14][15][16][17][18][19], and has also benefitted patients with graft versus host disease (GVHD) [20], Hepatitis C virus-induced vasculitis ...