Fine tuning of the innate and adaptive immune responses by Interleukin-2

Figures & data

Figure 1. Cellular source and functions of IL-2 in the thymus, periphery, and gut. In the thymus, (a) DCs bearing antigen secrete IL-2, which drives the development of T_reg cells, but also (b) T-cells are shown to promote the T_reg cell development and homeostasis. In periphery, (a) T effector cells act in an autocrine manner, producing IL-2, and thus regulating their proliferation and differentiation. Further, (b) T_reg cell homeostasis is maintained due to IL-2 paracrine signaling, where IL-2 suppression and elevated CD25 expression enhance the T_reg cell self-renewal and metabolic activity. Lastly, (c) mature DC, bearing antigen, release IL-2 that enhances T cell proliferation. In the gut, (a) endogenous IL-2 by conventional T-cells maintains tolerance, but also it has been shown that (b) CD103⁺ DC are able to induce the development of T_reg cells, via IL-2 secretion. This figure was created with Biorender.com.

Figure 2. Proposed interactions between DC and other immune cells in the TME, following IL-2 immunotherapy. Upon IL-2 administration, T-effector cells, ILCs and NK cells expand the cDC1 population in the tumor microenvironment, through the increased production of FLT3L, CSF-2 and TNF. Subsequently, cDC1-mediated IL-2 secretion aids the NK cell production of IFNγ, TNFα and GM-CSF. In this bi-directional crosstalk, NK cells further recruit cDC1 cells which lead to a concomitant increase in the cDC2 population, leading to an anti-tumoral priming of cytotoxic CD8⁺ T-cells and CD4⁺ T-cells respectively. A combinatorial treatment with IL-2 and for example anti-CD40 or all-trans retinoic acid, has shown that DC are able to promote a T_reg cell homeostasis in the TME, following DC-derived IL-2 secretion, and an inhibition of suppressive cell populations like MDSC, further augmenting the anti-tumoral immune response. This figure was created with Biorender.com.