Role of LFA‐1/ICAM‐1 in interleukin‐2‐stimulated lymphocyte proliferation

Abstract

Major adhesion routes between lymphoid cells involve the receptor/ligand pairs LFA-l/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 a or ¡3 subunit of LFA-1 or to its ligand ICAM-1. Interestingly, rIL-2-induced proliferation was also inhibited by NKI-L16, an anti-la antibody known to enhance cell-cell interac tion. 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-l/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-rnediated responses. Furthermore, it was shown that the rIL-2 response of T lymphocytes, but not of natural killer cells, was dependent on LFA-l/ICAM-1 interaction. This suggests that LFA-l/ICAM-1 interaction is required for an optimal iiL-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 responsive ness.

Interleukin-2 induces β2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB)

“…IL-2-induced homotypic adhesion in antigen-specific CD4 ϩ T cells and EDTA almost completely blocked the adhesion response ( Fig. 1 A) supporting other data (18)(19)(20) that ␤ 2 integrins play a crucial role in IL-2-induced adhesion. Because IL-2 induces tyrosine phosphorylation of an unidentified protein that was hypothesized to play a role in IL-2-induced adhesion (27), we examined whether EDTA modulated IL-2-mediated tyrosine phosphorylation.…”

“…An antibody against the ␤ 2 integrin ligand, CD54, also blocked IL-2-mediated induction of the 125-kDa phosphotyrosine protein. Because both mAbs inhibit IL-2-induced homotypic adhesion (18)(19)(20)(21)(22), our data suggest that ␤ 2 -integrin-dependent adhesion was involved in cytokine-induced tyrosine phosphorylation of the 125-kDa protein. This conclusion was supported by our findings that EDTA, an inhibitor of integrin-dependent adhesion, almost completely blocked both the IL-2 adhesion response and the induction of the 125-kDa phosphotyrosine protein.…”

“…Surprisingly, at high cell densities IL-2 induced comparable levels of proliferation in ␤ 2 -integrin-positive and -negative T cells, indicating that under these experimental conditions, ␤ 2 -integrin-dependent adhesion and tyrosine phosphorylation of fakB were not a prerequisite for induction of proliferation. Because ␤ 1 integrin molecules are also involved in IL-2-induced adhesion (18)(19)(20) and expressed by LAD T cell lines (data not shown), it is possible that at high cell densities, ␤ 1 integrins can provide comitogenic signals in ␤ 2 -integrinnegative LAD T cell lines.…”

“…Thus, IL-2 induces homotypic adhesion among T cells and binding of T cells to and migration across specialized and nonspecialized endothelia (17)(18)(19)(20). The adhesion response to IL-2 appears to be mediated primarily by ␤ 2 integrins (CD11a͞CD18) (18)(19)(20). However, it is not clear how IL-2Rs are functionally linked to the ␤ 2 integrin adhesion pathway and whether crosstalk takes place between ␤ 2 integrins and IL-2R.…”

Lysis of allogeneic and autologous melanoma cells by IL-7-induced lymphokine-activated killer cells

“…Differences in the responsiveness to IL-2 and IL-7 activation of NK cells could be another reason. However, other mechanisms, such as the induction of co-stimulatory signals, including adhesion molecules, as described recently (Altomonte et al, 1993;Piali et al, 1993;Poggi et al, 1993;Vyth-Dreese et al, 1993), have to be considered. Such a mechanism might help to explain the high autologous cytotoxicity generated by IL-7 observed in 2/5 of our patients (K.I.…”