IL-2: a two-faced master regulator of autoimmunity

Abstract

CD4(+) T-cell (Th) cytokines provide important regulatory and effector functions of T-cells. Among them, IL-2 plays a unique role. IL-2 is required for the generation and maintenance of regulatory T-cells (Treg) to provide lifelong protection from autoimmune disease. Whether IL-2 is also required for autoimmune disease development is less clear as Il2(-/)(-) mice themselves spontaneously develop multi-organ inflammation (MOI). In this communication, we discuss evidence that support the thesis that IL-2 is required for the development of autoimmune response, although some aspects of autoimmune response are not regulated by IL-2. Potential IL-2-dependent mechanisms operating at specific stages of the inflammation process are presented. The interplays among Treg, IL-2, autoimmune response and adaptive immunity are discussed. Overall, available information indicates that IL-2 is a two-faced master regulator of autoimmunity: one to prevent autoimmunity while the other promotes autoimmune response. The latter is an unfortunate consequence of IL-2 function that is used to promote the adaptive immune response against foreign antigens and pathogens.

Fig. 1

Treg control of peripheral tolerance: Self Ag are abundant and are always presented by APC. The number of nTreg as a whole is large. In contrast, the number of self Ag-reactive Tconv cells is small as a result of deletion by thymic negative selection. The check-and-balance between the two opposing reactions eventually reaches equilibrium such that a background but non-harmful co-existence of self Ag-reactive Tconv and nTreg is maintained.

Fig. 2

Induction of foreign Ag-specific response: When sufficient foreign Ag is picked up and processed by APC, it competes with self Ag for the MHC and replaces the self Ag to form foreign Ag-MHC complex. This results in loss of Treg and increase in foreign Ag-specific Tconv cells on the APC. The loss of Treg allows the activation of the foreign Ag-specific Tconv cells. As the reaction progresses and proceeds to its later stage, IL-2 and TGF-β1 are produced and the foreign Ag level becomes low. The condition favors the production of foreign Ag-specific iTreg and the return of the nTreg binding to the APC and its competitive suppressing activity.

Fig. 3

A general scheme of IL-2 regulated autoimmune response in Sf mice: Self Ag in organs are picked up by APC and enter the draining lymph nodes through lymphatic. In the lymph nodes, they prime the self-reactive Tconv cells. As a result of total absence of Treg, the activation cannot be contained. In the presence of IL-2, both Th1 and Th2 responses are activated and a large array of trafficking receptors (TrR) is induced. These T-cells travel through blood, and depending on their receptor expression, enter specific target organs. In the target organs, their activation by local APC induces the production of effector cytokines and inflammation. In the Sf.Il2^−/− mice, priming of both Th1 and Th2 cells occurs in the lymph nodes but the critical trafficking receptors for infiltrating skin and lungs are not induced. This effect coincides with the absence of skin and lung inflammation in Sf.Il2^−/− mice. However, Sf.Il2^−/− mice still display inflammation in the liver, pancreas, submandibular gland and colon. Due to the lack of IL-2, the inflammation in these organs is likely to be dominated by Th1 response.