Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R.

Abstract

SummaryInterleukin 2 (I1:2) receptors expressed on the surface of activated T cells and natural killer (NK) cells exhibit a variety of affinity states depending on their subunit composition. Low-affnity binding is associated with a 55-kD c~ chain, intermediate-affnity binding with a 70-75-kD chain, and high-affnity binding with a bimolecular complex of the c~ and fl subunits. In a previous study of the 1I:2 receptors expressed on NK cells obtained from cancer patients after in vivo I1.2 therapy, we documented a discrepancy between the level of fl chain and the level of intermediateaffinity I1.-2 binding sites expressed on the cell surface. Based on this result, we postulated that formation of intermediate-affnity receptor sites required a component in addition to the ~ chain, and that this component was present at limiting levels in the patient NK cells. In the present study we have examined the structure of the intermediatc*affnity receptor complex using monoclonal antibodies that recognize the fl chain, but that do not interfere with its ability to bind I1-2. Evidence is presented establishing the physical association of a novel protein of 64 kD with the chain in intermediate-affnity I1-2 binding sites. This molecule, termed I1.2R 3' chain, coprecipitated with B chains prepared from cells that had been incubated with I1.2, but was undetectable in immunoprecipitates prepared in the absence of I1-2. Examination of 3' chain expression in post-I1-2 therapy NK cells, where only low levels ofintermediate-affnity I1-2 binding were detectable, revealed that the 3~ chain was associated with, on average, only 10-12% of the 3 chains expressed on such cells. This contrasted with approximately equal levels of ~ and 3' chain expression on YT cells, a cell line that has both high levels of cell surface/~ chain expression and high levels of I1-2 binding. Thus, the ratio of 7 chain to ~ chain present in the immunoprecipitates roughly correlated with the proportion of/3 chain involved in intermediate-affnity receptor sites. This result suggests that the 64-kD 3~ chain is the component responsible for regulating the affinity of I1-2 association with the/~ subunit. By further defining the structural components necessary for I1-2 receptor formation, these studies provide additional insight into mechanisms whereby lymphocytes might regulate their responsiveness to IL-2. I 1.2 is a 15-kD glycoprotein produced by activated helper T lymphocytes that is responsible for activating and maintaining proliferative and cytolytic responses mediated by both T and NK cells (1-3). These cells are activated by soluble I1.-2 after its interaction with specific cell surface receptors. The I1.2R is made up of at least two subunits, o~ (p55, Tac) and ~ (p70-75), that noncovalently associate on the cell surface to produce a high-affnity receptor complex capable of binding II.-2 with an equilibrium Ka of ~5-20 pM (4-9). Each of the chains present in the I1.2R complex can bind I1.2 independently of the other, with either low (o~, Kd = 5-20 nM) or interm...

Endogenous IL-15 might be responsible for early protection by natural killer cells against infection with an avirulent strain of Salmonella choleraesuis in mice

“…NK and ␥␦ T cells are bone marrow-derived lymphocytes that constitutively express the ␤ and ␥c subunits of the IL-2R as a heterodimer with intermediate affinity for IL-2 [21,22]. Mice lacking IL-2R␤ or IL-2R␥ common (␥c) do not have NK or ␥␦ T cells [23][24][25][26], whereas mice lacking IL-2 have appreciable numbers of NK and ␥␦ T cells [27].…”

Analysis of IL-2 receptor expression and of the biological effects of IL-2 gene transfection in small-cell lung cancer

“…IL-2 mediates its stimulatory effects on T cells via a specific high-affinity receptor that is composed of at least three different chains involved in IL-2 binding, termed IL-2R a (CD25, p55 or TAC antigen), ,B (p75) and y (Taniguchi and Minamy, 1993). In addition, a functional IL-2R molecule, displaying lower affinity, composed of IL-2R # and y chains, is constitutively expressed on natural killer (NK) cells and on some T cell subsets (Voss et al, 1992). Expression of IL-2R chains has been reported not only on lymphoid cells but also on different human tumours, including squamous carcinoma (Weidmann et al, 1992;Yasumura et al, 1994), melanoma Rimoldi et al, 1993) and others (McMillan et al, 1995).…”

SIL index, comprising stage, soluble interleukin‐2 receptor, and lactate dehydrogenase, is a useful prognostic predictor in diffuse large B‐cell lymphoma

“…(3,4) Activated T cells, activated B cells, and some tumor cells are also known to induce sIL-2R expression. Soluble interleukin-2 receptor exists in healthy individuals at low levels; the upper limit of the normal range is approximately 500 U/mL.…”