Cyclosporine A has long been known to suppress T cell responses by inhibiting the production of IL-2, which drives T cell proliferation, enabling its use as a therapeutic for transplantation or autoimmunity.
The common gamma chain (γ<sub>c</sub>) contributes to the formation of different cytokine receptors [e.g., IL-2 receptor (IL-2R), IL-7R, and IL-15R], which are important for generation of self-reactive T-cells in autoimmune diseases, like in type 1 diabetes (T1D).
Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells.
Interleukin 2 (IL-2) is critical for T cell development and homeostasis, being a key regulator of adaptive immune responses in autoimmunity, hypersensitivity reactions and cancer.
Excitingly, the use of low-dose IL-2 for patients suffering from graft-<i>versus</i>-host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes.
Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.
Based on the characteristic properties of Treg cells such as constitutively expression of high affinity IL-2 receptors (IL-2Rs), multiple approaches, including IL-2/mAb complexes, IL-2 muteins and low-dose of IL-2 have emerged in recent years to selectively target Treg cells and treat autoimmunity.
As a consequence of Sos1/2 deficiency, production of the cytokine IL-2 was impaired, differentiation into regulatory T cells was reduced, and the autoimmune disease EAE was exacerbated in mice.
At the same time, low-dose IL-2 could decrease the ratio of Th17/CD4 Treg in short time, low-dose IL-2 can be used to treat autoimmune diseases to avoid adverse reactions caused by immunosuppressants.
MicroRNA 182 is important for the clonal expansion of CD4<sup>+</sup> T cells (Th) following IL-2 stimulation and is a potential therapeutic target for autoimmune diseases.
Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS.
Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases.
IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy.
The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases.
Since the successful clinical trials of IL-2 to treat patients with autoimmune diseases and inflammatory conditions, including Systemic lupus erythematosus (SLE) and Type 1 Diabetes (T1D), ld IL-2 therapy is a promising strategy to treat autoimmune diseases.
Work has been underway to establish ideal methods to integrate Tregs into the management of autoimmune diseases and alloimmunity, either by treatment with IL-2 or infusion of ex-vivo expanded Tregs.
We also summarize proof-of-concept clinical trials which have shown that low-dose IL-2 can control autoimmune diseases safely and effectively by specifically expanding and activating Treg.
The contribution of Tregs in autoimmune disease has opened up a new therapeutic avenue based on restoring a healthy balance between Tregs and effector T-cells, such as Treg-based cellular transfer or low-dose IL-2 modulation.
These basic mechanistic studies have led to the therapeutic ability to manipulate the action of IL-2 on regulatory T (T<sub>reg</sub>) cells for the treatment of autoimmune disease and on CD8<sup>+</sup> T cells for immunotherapy of cancer.