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Role of LFA-1/ICAM-1 in interleukin-2-stimulated lymphocyte proliferation
F A Vyth-Dreese1, T A Dellemijn, A Frijhoff
1Division of Immunology, The Netherlands Cancer Institute, Amsterdam.
Insights
Lymphocyte proliferation stimulated by interleukin-2 (IL-2) relies on LFA-1/ICAM-1 interactions. This adhesion pathway is crucial for T-cell responses to IL-2, particularly at early stages and low doses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Lymphoid cell adhesion is mediated by receptor/ligand pairs like LFA-1/ICAM-1.
- Interleukin-2 (IL-2) is a key cytokine for lymphocyte proliferation and immune responses.
Purpose of the Study:
- To investigate the role of major adhesion receptors in IL-2-induced lymphocyte proliferation.
- To elucidate the specific pathways through which adhesion molecules influence IL-2 signaling.
Main Methods:
- Utilized blocking monoclonal antibodies (mAbs) against adhesion molecules (LFA-1, ICAM-1, CD2, LFA-3).
- Assessed the impact of these mAbs on recombinant IL-2 (rIL-2)-induced lymphocyte proliferation.
- Differentiated between IL-2 receptor (IL-2R) subtypes (p55 and p75) and cell types (T lymphocytes, NK cells).
Main Results:
- Monoclonal antibodies against LFA-1 or ICAM-1 selectively inhibited rIL-2-induced proliferation.
- This inhibition was most pronounced in resting lymphocytes, early culture phases, and low rIL-2 doses.
- LFA-1/ICAM-1 interaction was essential for p55 IL-2R signaling but not p75 IL-2R responses.
- T lymphocyte responses to rIL-2, unlike NK cells, were dependent on LFA-1/ICAM-1 interaction.
Conclusions:
- LFA-1/ICAM-1 adhesion is critical for optimal T lymphocyte proliferation and response to IL-2.
- Adhesion receptor engagement may facilitate localized IL-2 release, enhancing high-affinity IL-2R signaling.
- This mechanism potentially up-regulates the p55 IL-2R, boosting overall cytokine responsiveness.
Abstract:
Major adhesion routes between lymphoid cells involve the receptor/ligand pairs LFA-1/ICAM-1 and CD2/LFA-3, in addition to VLA or CD44 molecules. In this study we evaluated the role of these adhesion receptors in the proliferative response of lymphoid cells to interleukin-2 (IL-2). Blocking studies were performed with a panel of monoclonal antibodies (mAb) directed against these adhesion molecules. Selective inhibition of recombinant (r)IL-2-induced cell proliferation was observed with mAb directed against the alpha or beta subunit of LFA-1 or to its ligand ICAM-1. Interestingly, rIL-2-induced proliferation was also inhibited by NKI-L16, and anti-1 alpha antibody known to enhance cell-cell interaction. Resting lymphocytes were preferentially susceptible to the inhibition, particularly in an early phase of culture and when stimulated with a relatively low dose of rIL-2. By using mAb that specifically could block distinct rIL-2 activation pathways, LFA-1/ICAM-1 interaction was found to be required for p55 IL-2 receptor (IL-2R)-mediated interaction of rIL-2 with its high-affinity receptor, but not for p75 IL-2R-mediated responses. Furthermore, it was shown that the rIL-2 response of T lymphocytes, but not of natural killer cells, was dependent on LFA-1/ICAM-1 interaction. This suggests that LFA-1/ICAM-1 interaction is required for an optimal rIL-2 response of cells capable of IL-2 secretion. Our data provide evidence for the hypothesis that adhesion receptor-directed release of IL-2 may result in a locally high concentration of IL-2 that triggers high-affinity IL-2R signaling and up-regulates p55 IL-2R to enhance cytokine responsiveness.