Lymphokine production by cells of the immune system can be initiated by cross-linkage of cell surface receptors. This is particularly striking for T cells where the relevant receptors are the alpha/beta or gamma/delta cell receptors, for mast cells where the receptors involved are Fc(epsilon)Rl and Fc(gamma)RII, and for NK cells where the receptor involved is Fc(gamma)RIII. The production of lymphokines mediated in this way is strikingly modulated by the presence of lymphokines; interleukin-4 (IL-4) production by naive T cells is strikingly enhanced by IL-2 while IL-4 production by cells of the mast cell lineage has a requirement for IL-3. Mast cell production of IL-4 and of other lymphokines, such as IL-3, depends upon cross-linkage of Fc receptors. For lymphokine production in response to Fc(epsilon)Rl cross-linkage, there are several very interesting features. Lymphokine secretion can be detected within about 1 hr of stimulation, requires continued presence of the cross-linking stimulus and is inhibited by excessive cross-linkage. IL-3 and IL-4 production by these cells is markedly enhanced by pretreatment of the cells with high concentrations of IL-3. Low concentrations of IL-3 or IL-4, although they cause the cells to grow, do not prepare them to produce IL-3. Similar effects have been observed in normal cells; IL-4 production by Fc(epsilon)RI+ cells in response to receptor cross-linkage is strikingly enhanced by pretreatment with IL-3. The functions of IL-4 are mediated by binding to a high affinity receptor. The major molecular species that is cross-linked to membrane-bound (125)I-IL-4 is a 70,000 dalton molecule (p7O) while the major IL-4 binding molecules purified from cell lysates or from membrane-labelled cells have weights of 120,000 (pl2O) and of 40,000 (p4O). The former is the major form of the cell surface receptor; the latter appears to be a secreted form of the receptor. The nature of p7O has been enigmatic. We have shown that p7O has a peptide map, for (125)I-IL-4-bound peptides, similar to pl2O, implying that it is a fragment of pl2O but the conditions under which this fragment is generated and its physiologic significance remain to be established.
