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Published on: February 28, 2019
Chemoattractant activity of IL-2 for human lymphocytes: a requirement for the IL-2 receptor beta-chain
1Immunology Department, University of Glasgow, U.K.
Insights
Recombinant human interleukin-2 (IL-2) drives lymphocyte locomotion and chemotaxis, primarily through the IL-2 receptor beta-chain. This pathway is crucial for immune cell movement and activation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Interleukin-2 (IL-2) is a cytokine critical for immune responses.
- Lymphocyte migration and activation are key processes in adaptive immunity.
- The IL-2 receptor (IL-2R) complex, comprising alpha and beta chains, mediates IL-2 signaling.
Purpose of the Study:
- To investigate the role of IL-2 in stimulating human lymphocyte locomotion and chemotaxis.
- To identify the specific IL-2 receptor subunit(s) responsible for mediating these IL-2-induced responses.
- To elucidate the signaling pathways involved in IL-2-driven lymphocyte migration.
Main Methods:
- Assays for lymphocyte shape change, chemotactic gradient orientation, and collagen gel invasion were employed.
- Recombinant human IL-2 was used to stimulate lymphocyte migration.
- Antibodies targeting IL-2 receptor alpha (IL-2R alpha) and beta (IL-2R beta) chains were used as inhibitors.
- Protein tyrosine kinase (PTK) inhibitor herbimycin was used to probe signaling pathways.
Main Results:
- IL-2 significantly stimulated lymphocyte locomotion and chemotaxis, outperforming IL-8 and MIP-1 alpha at optimal concentrations.
- Lymphocyte activation by FCS, anti-CD3, or PPD enhanced the proportion of IL-2 responsive cells.
- Anti-IL-2R beta completely inhibited IL-2-stimulated locomotion in both resting and activated lymphocytes.
- Anti-IL-2R alpha showed minimal inhibition, suggesting the beta-chain is the primary mediator.
- Herbimycin pretreatment inhibited IL-2 responses, indicating a role for protein tyrosine kinases.
Conclusions:
- The beta-chain of the IL-2 receptor is essential for IL-2-mediated activation of lymphocyte locomotion.
- Binding of IL-2 to the IL-2R beta-chain alone is sufficient to trigger lymphocyte migration.
- Protein tyrosine kinase signaling downstream of IL-2R beta engagement regulates cytoskeletal activity for cell movement.
Abstract:
Recombinant human interleukin-2 (IL-2) stimulated locomotion and chemotaxis of human blood lymphocytes as measured by shape change to a polar morphology, by orientation in a chemotactic gradient, and by a collagen gel invasion assays. IL-2 stimulated locomotion of a larger number of lymphocytes than IL-8 or macrophage inflammatory protein (MIP)-1 alpha, but the maximally effective concentration of all three was similar (around 100 ng/ml). Activation of the lymphocytes by culture for 24-48 hr in fetal calf serum (FCS), anti-CD3, or purified protein derivative (PPD) increased the proportion of responsive cells, though even direct from blood, > 20% of lymphocytes showed locomotor responses to IL-2, a figure which was similar to the number of IL-2 receptor (IL-2R) beta+ lymphocytes but higher than the number of IL-2R alpha+ cells. The effect of antibodies to IL-2R alpha and IL-2R beta as inhibitors of these responses was therefore tested. Anti-IL-2R beta (alpha IL-2R beta) completely inhibited the response of both resting and activated cells: alpha IL-2R alpha had no inhibitory effect on the locomotion of lymphocytes direct from blood, and only partially inhibited locomotion after culture for 48 hr in alpha CD3 or PPD. The locomotor response to IL-2 was inhibited by pretreatment of the cells with herbimycin, a protein tyrosine kinase (PTK) inhibitor, an observation consistent with PTK control of cytoskeletal activity following binding of IL-2 to IL-2R beta. These results suggest that the beta-chain of the IL-2R is required for activation of lymphocyte locomotion by IL-2 and that binding of IL-2 to this chain alone is sufficient for a response.
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