IL7 - interleukin 7 |Elisa - Clia - Antibody - Protein

Background

Interleukin-7 (IL-7) is a critical cytokine primarily involved in the development, survival, and homeostasis of immune cells, particularly T cells and B cells. It plays an essential role in lymphopoiesis, ensuring the proper function and maintenance of the adaptive immune system. IL-7 is produced mainly by stromal cells in the bone marrow and thymus, but it is also secreted by epithelial cells in other tissues, such as the intestines, liver, and skin. Unlike many cytokines, IL-7 is not produced by immune cells themselves but acts as a growth factor necessary for immune cell survival and proliferation.

IL-7 is vital for the survival of naïve and memory T cells, supporting the homeostasis of these populations throughout life. It also supports the early stages of B cell development in the bone marrow and ensures the development of a healthy and functional immune system. IL-7’s function in maintaining T cell homeostasis and supporting immune recovery has made it a target of interest in immunotherapy, particularly for treating immune deficiencies, enhancing cancer immunotherapy, and facilitating immune reconstitution in HIV patients.

Protein Structure

IL-7 is a small glycoprotein with a molecular weight of approximately 25 kDa, consisting of 177 amino acids. The structure of IL-7 is characterized by a four-helix bundle typical of the class I cytokine family, which also includes IL-2, IL-4, and IL-9. This cytokine adopts a compact, globular shape supported by two disulfide bonds that are essential for maintaining its structural integrity and biological activity.

Key elements of IL-7’s structure include:

• Four-Helix Bundle: Like other cytokines in the class I family, IL-7 consists of four alpha-helices that fold into a stable bundle structure. This arrangement is critical for its function, as it provides the necessary conformation for binding to its receptor.
• Disulfide Bonds: IL-7 contains two critical disulfide bonds that stabilize its tertiary structure. These bonds are located between cysteine residues at conserved positions in the molecule and are essential for the cytokine's stability and proper receptor interaction.
• Receptor Binding: IL-7 exerts its biological effects by binding to the IL-7 receptor (IL-7R), which is a heterodimer consisting of two subunits:

1. IL-7Rα (CD127): The alpha chain of the IL-7 receptor, which is specific to IL-7 and IL-7-like cytokines such as thymic stromal lymphopoietin (TSLP).
2. γc (Common gamma chain): A shared receptor subunit used by other cytokines, including IL-2, IL-4, IL-9, IL-15, and IL-21.

The interaction of IL-7 with IL-7Rα initiates the recruitment of the γc subunit, leading to receptor dimerization and activation of intracellular signaling pathways, primarily the JAK/STAT (Janus kinase/Signal Transducer and Activator of Transcription) pathway. This signaling cascade is crucial for the promotion of cell survival, proliferation, and differentiation.

Classification and Subtypes

IL-7 is a member of the class I cytokine family, which is characterized by cytokines that adopt a four-helix bundle structure and signal through receptors containing the common gamma chain (γc). IL-7 is classified as a hematopoietic growth factor due to its role in lymphocyte development and homeostasis.

Though IL-7 does not have distinct subtypes, it shares functional similarities with other cytokines like:

• Thymic Stromal Lymphopoietin (TSLP): TSLP is closely related to IL-7 in terms of structure and receptor usage. While IL-7 is primarily involved in lymphocyte homeostasis, TSLP is more active in promoting immune responses at barrier tissues and is involved in allergic inflammation.

Function and Biological Significance

IL-7 is indispensable for the immune system, with its primary biological functions focused on the development and maintenance of T cells and B cells. Key roles of IL-7 include:

1. T Cell Development: IL-7 is essential for the survival and proliferation of developing T cells in the thymus, particularly at the double-negative (CD4-/CD8-) and double-positive (CD4+/CD8+) stages of T cell maturation. Without IL-7, thymocyte survival is impaired, leading to defective T cell development and immune deficiency. Once T cells have matured and exited the thymus, IL-7 remains crucial for the survival of naïve T cells, which circulate through the body awaiting antigen recognition.
2. B Cell Development: During early B cell development in the bone marrow, IL-7 acts as a growth factor that supports the proliferation of pro-B and pre-B cells. Although its role diminishes after B cells mature, it is essential for establishing a functional B cell population in early immune development.
3. T Cell Homeostasis: IL-7 is fundamental for the maintenance of peripheral T cell populations, particularly in the naïve and memory T cell compartments. Naïve T cells, which have not yet encountered their specific antigen, rely on IL-7 for survival signals, preventing apoptosis during their long lifespan. Memory T cells, which persist after an immune response to provide long-term immunity, also depend on IL-7 for their maintenance.
4. Regulation of T Cell Activation and Proliferation: IL-7 contributes to the expansion of T cells following antigen recognition. When T cells encounter a pathogen, IL-7 helps promote their proliferation and differentiation, ensuring a robust immune response. This function is particularly important during periods of lymphopenia (low lymphocyte counts), where IL-7 levels increase to stimulate immune reconstitution.
5. Immune Recovery: IL-7 has a unique ability to promote immune reconstitution following immunosuppression or immune depletion, such as in patients recovering from chemotherapy, bone marrow transplants, or HIV infection. IL-7 enhances the expansion of both CD4+ and CD8+ T cells, making it a promising candidate for therapeutic interventions aimed at restoring immune function.
6. Lymphopenia-induced IL-7 Elevation: IL-7 levels are inversely correlated with the size of the T cell pool. In conditions of lymphopenia, where T cell numbers are reduced (such as after chemotherapy or infection), IL-7 levels increase in circulation to stimulate T cell recovery. This adaptive mechanism is crucial for reestablishing immune homeostasis after immune system insults.

Clinical Issues

Given its central role in lymphocyte biology, dysregulation of IL-7 or its signaling pathways can lead to various clinical issues, particularly in immune deficiencies, autoimmune diseases, and cancers. Therapeutic modulation of IL-7 has emerged as a potential strategy for treating these conditions.

1. Severe Combined Immunodeficiency (SCID): IL-7Rα deficiency is one of the genetic causes of SCID, a group of disorders characterized by profound immune deficiency due to defects in T cell development. Patients with IL-7Rα mutations have impaired thymocyte survival, leading to a lack of functional T cells, although B cell development may be less affected. Gene therapy or bone marrow transplantation can restore immune function in these patients.
2. HIV and T Cell Reconstitution: In HIV infection, the virus depletes CD4+ T cells, leading to immune system failure. IL-7 levels are often elevated in HIV-infected individuals due to the lymphopenic environment. Clinical trials using recombinant IL-7 have shown promise in enhancing T cell recovery and improving immune function in HIV patients, particularly during antiretroviral therapy (ART).
3. Cancer Immunotherapy: IL-7 has emerged as a potential adjuvant in cancer immunotherapy, where boosting T cell numbers and function is critical. Administering IL-7 can increase the proliferation and survival of tumor-specific T cells, enhancing their ability to target and eliminate cancer cells. This approach is being investigated in combination with other immunotherapies, such as checkpoint inhibitors.
4. Autoimmune Diseases: While IL-7 is essential for normal immune function, dysregulation of IL-7 signaling has been implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS). In these conditions, excessive IL-7 may promote the survival and proliferation of autoreactive T cells, leading to immune-mediated tissue damage. Blocking IL-7 or its receptor could provide a therapeutic approach to dampen autoimmune responses.
5. Therapeutic Potential: Recombinant IL-7 is being explored as a therapeutic agent in conditions requiring immune system regeneration. IL-7 therapy has shown benefits in restoring T cell populations in settings of lymphopenia, such as after chemotherapy, bone marrow transplantation, and viral infections. Its ability to enhance immune recovery without overstimulating inflammation makes IL-7 an attractive candidate for clinical use.

Summary

IL-7 is a crucial cytokine involved in the development, survival, and homeostasis of T and B cells, with a particular focus on lymphocyte survival during immune development and homeostasis. Structurally, it is a small glycoprotein characterized by a four-helix bundle and stabilized by disulfide bonds, which bind to the IL-7 receptor complex composed of IL-7Rα and the common gamma chain (γc). Functionally, IL-7 is indispensable for T cell development in the thymus, B cell maturation in the bone marrow, and the maintenance of naïve and memory T cells in peripheral circulation. Clinically, IL-7 dysregulation is linked to immune deficiencies like SCID, autoimmune diseases, and it has therapeutic potential in immunodeficiency recovery, cancer immunotherapy, and HIV treatment. Understanding the biological role of IL-7 has opened new avenues for targeted therapies aimed at modulating immune responses in both disease and therapeutic contexts.