IL7R - interleukin 7 receptor| Elisa - Clia - Antibody - Protein

Background

The interleukin-7 receptor (IL7R) is a critical component of immune system regulation, playing a major role in the development, survival, and homeostasis of T cells and, to a lesser extent, B cells. It is encoded by the IL7R gene and consists of two distinct subunits: IL-7Rα (CD127), which is unique to the IL-7 receptor, and γc (CD132), a common gamma chain shared with other cytokine receptors such as those for IL-2, IL-4, IL-9, IL-15, and IL-21. IL-7, the ligand for IL7R, is an essential cytokine that provides survival signals to developing lymphocytes and regulates their function, influencing T cell diversity, immune tolerance, and immune responsiveness.

The IL7R signaling pathway has profound effects on immune system homeostasis, enabling it to counteract immune deficiencies, support immune recovery after depletion, and maintain immune memory. Dysregulation of IL7R, however, is implicated in a range of conditions, including severe combined immunodeficiency (SCID), autoimmune diseases, and certain cancers, especially T-cell acute lymphoblastic leukemia. The receptor’s pivotal role in lymphocyte biology makes it a significant target for immunological therapies and interventions.

Protein Structure

IL7R is a type I transmembrane receptor composed of approximately 439 amino acids. The structural domains of IL7R are organized to support ligand binding, receptor dimerization, and downstream signaling:

Extracellular Domain (ECD):

• The ECD comprises about 219 amino acids and includes a cytokine receptor homology domain (CRH) and a fibronectin type III-like domain, essential for IL-7 binding. This CRH domain, containing conserved cysteine residues and a "WSXWS" motif, provides structural stability, facilitating efficient ligand binding.
• The presence of N-linked glycosylation sites in the ECD enhances the receptor’s stability and functional conformation. The ECD binds to IL-7 with high affinity, initiating signaling processes essential for lymphocyte survival and proliferation.

Transmembrane Domain (TMD):

• The TMD is a short alpha-helical segment that anchors IL7R to the plasma membrane and is essential for dimerization with the common γc subunit, which stabilizes the receptor complex and enables efficient signal transduction.

Intracellular Domain (ICD):

• The ICD of IL7R, comprising approximately 195 amino acids, lacks inherent enzymatic activity but serves as a recruitment site for signaling molecules. Critical tyrosine residues within the ICD undergo phosphorylation upon IL-7 binding, allowing recruitment of Janus kinase 1 (JAK1), which subsequently activates STAT5 and other downstream signaling molecules essential for cell proliferation and survival.

Classification and Subtypes

IL7R belongs to the type I cytokine receptor family, specifically within the hematopoietin receptor superfamily, characterized by their conserved WSXWS motif in the ECD. Although IL7R has no subtypes, it forms a functional receptor complex with the common gamma chain (γc), which is also shared with receptors for other cytokines (IL-2, IL-4, IL-9, IL-15, and IL-21). This multi-cytokine sharing of the γc subunit is critical for lymphocyte signaling diversity, as it permits the receptor to integrate signals from various cytokines while relying on a single subunit for structural support and signaling.

Function and Biological Significance

IL7R is central to lymphocyte survival, development, and homeostasis. Key functions and biological roles of IL7R include:

T Cell Development and Homeostasis:

• IL7R signaling is essential for thymocyte development and the survival of naïve T cells, especially in peripheral tissues. During T cell maturation, IL-7/IL7R signaling promotes thymocyte proliferation and helps in the selection process, which determines the functional diversity and self-tolerance of T cells. In mature T cells, IL7R signaling provides the survival signals needed to maintain a diverse pool of T cells, supporting immune memory and tolerance.

B Cell Development:

• Although IL7R is less critical for B cell maturation in humans than in mice, IL-7 signaling does influence early B cell development in the bone marrow, supporting the growth and maturation of precursor B cells.

Maintenance of T Cell Memory:

• IL7R signaling is critical for the long-term survival of memory T cells, which allows the immune system to “remember” previously encountered pathogens and respond rapidly upon re-exposure. Memory T cells are characterized by sustained IL7R expression, enabling them to survive independently of antigen presence.

Immune Recovery and Homeostasis:

• In situations where lymphocytes are depleted (such as during infection, chemotherapy, or bone marrow transplantation), IL7R signaling helps promote immune system reconstitution. IL7R, therefore, plays a role in restoring lymphocyte populations and re-establishing immune equilibrium.

Regulation of T Cell Tolerance and Self-Renewal:

• IL7R signaling helps prevent autoimmunity by maintaining regulatory T cell populations and supporting central tolerance mechanisms during T cell selection. Furthermore, IL7R is involved in regulating T cell proliferation and self-renewal, ensuring that cell populations do not expand uncontrollably.

Clinical Issues

Dysregulation of IL7R or mutations in the IL7R gene are associated with various immunological conditions and malignancies:

Severe Combined Immunodeficiency (SCID):

• Mutations in the IL7R gene can lead to a form of SCID, known as T– B+ NK+ SCID, characterized by an absence of functional T cells but normal B and natural killer (NK) cells. Individuals with IL7R-deficient SCID suffer from severe immunodeficiency, leading to susceptibility to infections and requiring interventions such as hematopoietic stem cell transplantation (HSCT) for immune reconstitution.

Autoimmune Disorders:

• Polymorphisms in IL7R have been linked to an increased risk of autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). Altered IL7R signaling in these conditions may contribute to immune dysregulation, leading to an inappropriate immune response against self-antigens.

Cancer:

• Dysregulation of IL7R is observed in certain hematological malignancies, particularly T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL, activating mutations in IL7R lead to uncontrolled T cell proliferation and survival, contributing to cancer development. IL7R has been investigated as a potential target in therapeutic strategies for T-ALL, using inhibitors that block IL-7/IL7R signaling.

Immune Recovery Post-Chemotherapy or Transplantation:

• IL7R signaling is crucial for immune recovery in individuals who have undergone lymphodepleting therapies, such as chemotherapy or bone marrow transplants. IL-7 therapy is being explored as a potential treatment to accelerate T cell recovery and immune reconstitution, aiding patients in overcoming post-treatment immunodeficiency.

Summary

IL7R is a vital cytokine receptor involved in immune system development, homeostasis, and regulation. Structurally, IL7R is a type I transmembrane receptor with an extracellular domain for cytokine binding, a transmembrane segment, and an intracellular domain that recruits signaling molecules. This receptor pairs with the common gamma chain (γc) to form the functional IL-7 receptor complex, essential for T cell development, survival, and immune tolerance.

IL7R’s signaling pathways are integral to lymphocyte biology, facilitating the differentiation and maintenance of T cells and supporting early B cell development. Its role in maintaining memory T cells enables long-term immune memory, while its function in immune reconstitution aids recovery following lymphocyte depletion. However, mutations or polymorphisms in IL7R can lead to immune deficiencies like SCID, and dysregulated IL7R signaling contributes to autoimmune diseases and certain cancers, particularly T-ALL.

In clinical settings, targeting IL7R or modulating its signaling pathway is an area of ongoing research. The receptor's role in supporting immune recovery is being explored therapeutically for immune reconstitution in cancer and post-transplant patients. Given its central importance in immune system regulation, IL7R remains a focal point for understanding immune diseases and developing innovative immunotherapies.