IL-2 Immunology: Receptor Subunits, Signaling, and T-Cell Growth

Interleukin-2 (IL-2) is a critical cytokine in the immune system, primarily influencing T-cell proliferation, survival, and differentiation. Initially identified as a T-cell growth factor, IL-2 is now recognized for its broader role in immune regulation, including maintaining tolerance and modulating inflammation.

Its effects are mediated through a multi-subunit receptor complex that initiates intracellular signaling cascades. These pathways drive effector T-cell expansion while also supporting regulatory mechanisms that prevent autoimmunity. Understanding IL-2’s receptor composition, signaling dynamics, and functional outcomes provides insights into both normal immune responses and pathological conditions linked to dysregulated IL-2 activity.

Structure And Receptor Subunits

IL-2 exerts its effects through a receptor complex composed of three subunits: alpha (CD25), beta (CD122), and gamma (CD132). These subunits assemble in different configurations to regulate cytokine affinity and downstream signaling. Each plays a distinct role in ligand binding and signal transduction, shaping immune cell responsiveness.

Alpha Subunit

The IL-2 receptor alpha subunit (IL-2Rα or CD25) is a low-affinity component that enhances cytokine capture at the cell surface. Unlike the beta and gamma subunits, CD25 does not participate in intracellular signaling but instead increases the local concentration of IL-2, facilitating its interaction with the signaling-competent subunits. CD25 expression is highly inducible, with resting T cells exhibiting minimal levels, while activated T cells, regulatory T cells, and certain dendritic cells express it at elevated levels. This regulation allows immune cells to fine-tune their sensitivity to IL-2.

Structural studies show that CD25 forms an initial binding interface with IL-2, stabilizing the cytokine and positioning it for interaction with the signaling subunits. Therapeutically, CD25 has been targeted in conditions requiring IL-2 modulation. Monoclonal antibodies like basiliximab inhibit IL-2-driven T-cell activation and are used to prevent transplant rejection.

Beta Subunit

The IL-2 receptor beta subunit (IL-2Rβ or CD122) is a key signaling component, forming part of both the intermediate-affinity (IL-2Rβ/γ) and high-affinity (IL-2Rα/β/γ) receptor complexes. Unlike CD25, CD122 directly participates in intracellular signaling by recruiting Janus kinase 1 (JAK1) upon IL-2 binding. It is expressed on activated T cells and natural killer (NK) cells, allowing these populations to respond to IL-2 even in the absence of CD25.

Structural analyses show that CD122 facilitates IL-2 engagement with the gamma subunit, optimizing signaling. Mutations in CD122 have been linked to immune dysregulation syndromes, highlighting its role in cellular homeostasis. Engineered IL-2 variants selectively targeting CD122 are being explored for modulating immune responses in cancer and autoimmune diseases.

Gamma Subunit

The IL-2 receptor gamma subunit (IL-2Rγ or CD132) is an essential signaling component shared by multiple cytokine receptors, including those for IL-4, IL-7, IL-9, IL-15, and IL-21. This common gamma chain is crucial for signal propagation, as it associates with JAK3 to initiate downstream pathways like STAT5 phosphorylation. CD132 is widely expressed on hematopoietic cells, ensuring broad cytokine responsiveness.

Structural studies reveal that IL-2 binding induces a conformational shift stabilizing the IL-2Rβ/γ complex, triggering intracellular signaling. Genetic defects in CD132 result in X-linked severe combined immunodeficiency (X-SCID), underscoring its fundamental role in immune function. Therapeutically, targeting CD132-mediated signaling has been investigated in conditions such as graft-versus-host disease, where modulating IL-2 signaling can influence immune reconstitution.

Signal Transduction Mechanisms

IL-2 signaling begins when the cytokine binds its receptor complex, triggering intracellular events that regulate proliferation, survival, and gene expression. JAK1 associates with the beta subunit (CD122), while JAK3 binds the gamma subunit (CD132), forming a signaling-competent receptor complex. Activation of these kinases leads to STAT5 phosphorylation, enabling its dimerization and nuclear translocation, where it modulates gene transcription related to cell cycle progression and survival.

Beyond the JAK-STAT pathway, IL-2 receptor engagement activates phosphoinositide 3-kinase (PI3K) signaling, which regulates metabolic adaptation and survival. PI3K recruitment leads to the production of PIP3, activating Akt, which promotes cell survival by inhibiting pro-apoptotic factors and enhancing genes supporting growth. The mammalian target of rapamycin (mTOR) integrates IL-2 signals to regulate protein synthesis and metabolic activity, ensuring proliferating cells have sufficient energy and biosynthetic resources.

IL-2 also activates the Ras-MAPK pathway, influencing differentiation and proliferation. Recruitment of Grb2 and SOS to the receptor complex activates Ras, which triggers a cascade involving Raf, MEK, and ERK. This leads to phosphorylation of transcription factors like Elk-1 and c-Fos, promoting cell cycle progression. The integration of JAK-STAT, PI3K-Akt, and Ras-MAPK pathways ensures IL-2 stimulation results in a coordinated response balancing growth, survival, and differentiation.

Role In T-Cell Expansion

IL-2 drives T-cell expansion by providing signals for proliferation following antigen recognition. Once a naïve T cell encounters its cognate antigen through the T-cell receptor (TCR), it undergoes IL-2 production and receptor upregulation. IL-2 binding triggers intracellular events that transition the cell from a quiescent state to active proliferation.

IL-2 also modulates metabolic programming to sustain rapid proliferation. Activated T cells shift from oxidative phosphorylation to aerobic glycolysis, ensuring sufficient ATP and biosynthetic precursors for growth. IL-2 signaling through the PI3K-Akt-mTOR pathway enhances glucose uptake and amino acid metabolism, particularly in CD8+ T cells, where mTOR activation supports cytotoxic lymphocyte development. Without adequate IL-2 signaling, T cells fail to sustain growth, leading to impaired immune responses.

IL-2-mediated expansion is tightly regulated to prevent uncontrolled proliferation. Autocrine and paracrine IL-2 signaling create a competitive environment, ensuring antigen-specific T cells dominate while non-specific cells remain unaffected. Temporal regulation of IL-2 availability prevents excessive accumulation and promotes immune resolution.

Interplay With Regulatory T Cells

IL-2 is essential for regulatory T cells (Tregs), a subset that suppresses immune activation and preserves tolerance. Unlike conventional T cells, which use IL-2 for proliferation, Tregs depend on continuous IL-2 signaling for stability and suppressive function. Their high expression of CD25 allows them to efficiently capture IL-2, limiting its availability to effector T cells and modulating immune homeostasis.

IL-2 signaling in Tregs is primarily mediated through STAT5, which drives FOXP3 expression, the master transcription factor defining Treg identity. FOXP3 enhances immunosuppressive molecules like CTLA-4 and IL-10, enabling Tregs to dampen immune activation. IL-2 or receptor deficiencies lead to Treg loss and fatal autoimmunity, underscoring IL-2’s non-redundant role in immune regulation.

Interactions With Other Cytokines

IL-2 interacts with a network of cytokines that shape immune responses. Its relationship with IL-15 is particularly notable, as both share IL-2 receptor beta and gamma subunits. While both activate similar pathways, IL-15 maintains memory T cells and NK cells, whereas IL-2 drives activation-induced expansion. IL-2-deficient mice develop autoimmunity due to impaired Treg function, while IL-15-deficient mice exhibit defects in memory T-cell persistence and NK cell survival.

IL-2 also interacts with IL-10 and TGF-β, cytokines associated with immune regulation. IL-10 dampens IL-2-driven effector T-cell expansion, limiting inflammation while preserving function. TGF-β influences IL-2’s role in T-cell differentiation, particularly in balancing Tregs and Th17 cells. In the presence of IL-2, TGF-β enhances FOXP3 expression, favoring Tregs, whereas in its absence, it promotes Th17 differentiation, implicated in autoimmunity.

Implications In Autoimmune Conditions

Dysregulated IL-2 signaling is linked to autoimmune diseases. Reduced IL-2 availability or receptor signaling defects contribute to conditions like type 1 diabetes and systemic lupus erythematosus (SLE), where impaired Treg function allows autoreactive T cells to escape suppression. Low-dose IL-2 therapy selectively expands Tregs, promoting immune tolerance.

Conversely, excessive IL-2 signaling can lead to overactive Tregs, dampening protective immunity in chronic infections and cancer. Therapies modulating IL-2 levels must balance enhancing regulatory functions while maintaining sufficient effector responses. Modified IL-2 variants with altered receptor affinities show promise in selectively boosting Tregs while minimizing off-target effects, offering new avenues for precision treatments in autoimmune diseases.