Interleukin-2, Plasma

Cytokines are low-molecular-weight intercellular signaling molecules that are produced de novo in response to an immune stimulus.^1-3 They regulate immune cell homeostasis by mediating innate and acquired immunity, and inflammation in human health and disease. They generally (although not always) act over short distances and short time spans and at very low concentrations. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation and secretion of effector molecules. It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).

The cytokine Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses.⁴ IL-2 acts as a growth factor for T cells and serves as a key component of immune activation.^5-7 Somewhat paradoxically, gene knockout mouse studies have provided evidence that the primary IL-2 function in vivo is the suppression of T responses. Mice lacking IL-2 or its receptor develop lymphadenopathy and T cell-mediated autoimmunity.^5,8 Interleukin-2 receptor (IL-2R) signaling regulates tolerance and immunity with deficient signaling resulting in autoimmunity.^5,9 The therapeutic action of IL-2 is related to concentration. Low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating antitumor immune responses.^4,5

The cellular receptor for IL-2 is a three-chain molecule.⁵ The receptors signaling function is mediated by the beta and gamma chains, which are expressed on T cells (and natural killer cells) constitutively, can be up-regulated by activation and dimerize to bind IL-2 with low affinity.⁵ The alpha chain of the IL-2 receptor (CD25) has no signaling capacity but confers on the receptor the ability to bind IL-2 with high-affinity.⁵ T cell activation induces IL-2 production and upregulates the high-affinity IL-2 receptor subunit CD25, increasing T-cell responsiveness to IL-2.^5,9 Binding of IL-2 to its high-affinity receptor causes T cells to proliferate about 1,000-fold in the secondary lymphoid organs, producing a large population of lymphoblasts, also termed effector cells.¹⁰ IL-2 binding to its receptor stimulates increased cytokine synthesis and potentiates Fas-mediated apoptosis. It causes proliferation and activation of NK cells and B-cell proliferation and antibody synthesis. Also, it stimulates the activation of cytotoxic lymphocytes and macrophages.¹¹ IL-2R signaling influences two discrete aspects of immune responses by CD8(+) T cells, terminal differentiation of effector cells in primary responses and aspects of memory recall responses.⁹

IL-2 is produced mainly by CD4b helper T cells ⁵ and a subset of CD8 cells.¹² T cells that express high levels of CD25 are essential for maintaining self-tolerance. A class of T cells, known as regulatory T cells (Tregs), are defined by the co-expression of CD25 and the transcription factor forkhead box P3 (FOXP3).^5,9 Studies indicate that IL-2 not only stimulates immune responses and generates effector cells but also is required for Treg-mediated suppression of immune responses.⁵ A major and essential function of IL-2 is to maintain self tolerance and prevent autoimmunity, and depletion or decreased production of this cytokine is associated with systemic autoimmunity.⁵

Although exposure of a memory CD8 cells to their cognate antigen generally induces reactivation and cytotoxicity, sustained antigen exposure during chronic infection and cancer can cause exhaustion.¹³ Exhausted CD8 T-cells lose effector function, fail to self-renew and have defective memory responses. They are characterized by high expression of inhibitory receptors, expression of specific transcriptional regulators and metabolic dysfunction. While T cell exhaustion is undesirable in the setting of infection and malignancy, it can protect from autoimmunity. Both soluble and cellular mediators can regulate exhaustion in CD81 T-cells. IL-10 can induce exhaustion, whereas IL-2 can promote or repress exhaustion depending on the timing and duration of exposure.¹²

A meta-analysis found that elevated IL-2 was strongly associated with acute respiratory distress syndrome mortality.¹⁴