EGF and Viral Transformation 1

Nature Vol. 264 November 4 1976 13 toxic T cells (reactive to H-2 antigens) by the use of anti-la antiserum, which lyses the former, and also by anti-Ly- EGF and viral transformation 1. 1, which lyses cytotoxic cells of the from Robin A . Weiss CBA strain. On the other hand, the precursors of suppressor cells are EPIDERMAL growth factor (EGF) was (KNRK) and by Rous sarcoma virus usually not lysed by anti-la antiserum", dis,covered by Stanley Cohen (J. biol. (XC) apparently lacked EGF receptors. and thus the two cell types could still Chem., 237, 1555; 1962) when he was Reduction in the binding of other be closely related. purifying nerve growth .factor from hormones to transformed cells ha~ also clear, however, that the It is now the submaxillary salivary gland of male been reported, for example, in a recent Ly-1 and Ly-2 populations belong to mice. Cohen noted that the factor study of insulin receptors on BALB/ and ar.:: different lines of differentiation stimulated tihe .proliferation and dif 3T3 cells by Thomopoulous, Roth, Hne not sequential stages in a single ferentiation of the epidermis, as re Lovelace and Pastan (Cell, 8, 417; have age". Cantor and his colleagues flected by precocious opening of the 1976). The binding of insulin varied shown that mice depleted of T cells eyelids and eruption of the incisors in with the level of proliferation in cell (thymectomised, irradiated and bone baby mice. Since that time it has been population and the reduction seen in marrow-reconstituted mice or "B Cohen's remarkable aohievement to transformed dones was not specific to mice") and repopulated with Ly-1 T purify and sequence murine EGF the transforming agent. However, the cells only were not able ·to perform (Cohen and Savage, Recent Progress in ,presence of EGF receptors appears to any of the functions of Ly-2,3 cells, Hormone Research, 30, 551; 1974). It be more specific. In this issue of even many months later; and conversely is a single-chain polypeptide containing Nature (page 26), Cohen, in col "B mice" repopulated with Ly-2,3 cells 53 amino-acid residues with a mole la,boration with Todaro ,and De Larco, could express cytotoxicity and sup cular weight of 6,045. The molecule has reports additional data on the binding pression, but not other T cell functions. been well conserved during evolution of EGF to the same cell types trans There is great interest in the role and human EGF extracted from urine formed by different tumour viruses. of the major histocompatibility com shows only minor differences in amino For example, tJhe A3 I clone of m_ouse plex (MHC) in immune responses. One acid sequence to murine EGF. Re BALB/3T3 cells was transformed by aspect which has attracted attention is cently it has become evident that EGF SV 40, two strains of mouse sarcoma the prohibition of cell interactions will stimulate proliferation of a variety virus (MSV) and Rous sarcoma virus across allogeneic barriers where MHC of both epithelial and fibroblastic cells (RSV). Only the MSV-transformed differences are involved. This has been in culture. Its spec,ifk mitogenic action subdones foiled to bind EGF. This reported for T- B interactions by Katz on non--prolifemting cells in culture remarkable specificity of binding was and colleagues", for T-macrophage provides a much more convenient and true for transformed subclones of interactions by Rosenthal and Shevach" quantitative assay -than examining eye other types of cell such as Swiss 3T3, and Erb and Feldmann", and for T cell lid opening in vivo. NRK and Mink lung. In each case, killing, by Zinkernage1, Blanden and Last year Cohen's group showed that only the subclones transformed by Doherty'". Several explanations have cells in culture which respond to the MSV or by feline sarcoma virus failed been suggested for these restrictions. mitogenic action of EGF possess spe to bind EGF. One is that a molecule controlled by c,ific receptors for EGF on the cell Solely on the basis o.f the specific the MHC must be "shared" or recog surface (Canpenter, Lembach, Mor failure to bind EGF, the authors pos nised for successful interactions to rison and Cohen, J. biol Chem., 250, tulate that MSV might transform cells occur". An alternative suggestion is that 4297; 1975). EGF receptors were by coding for an EGF-like molecule in mixing histoincompatible cells may In assayed by measuring the binding of part of its sarcoma-specific genetic 11 EGF anafogue would duce activf" suppr,ession"· . D. H. Katz "'I-1,aibelled EGF to the cell surface. sequences. This (Harvard University), for example, Cells of many species bound EGF, but then block the receptors and stimulate found that suppressor cells are induced certain types, including a human lym the cells to grow. This will hardly pro when Fi thymocytes are primed in an phoblastoid line (NC-37) and rat cells vide the whole explanation of viral irradiated parental mouse. These sup transformed by mouse sarcoma virus oncogenesis, but it can be tested. pressor cells may explain the genetic restrictions on T-B collaboration found 13 D. B. Murphy, Stanford Uni in earlier ex,periments • Support for It now seems clear from the reports and this possibility was discussed by H. of several workers that suppression is versity). seem to be Cantor a·nd R. K. Gershon (Yale Uni mediated by products of the I region. T Two generalisations versity) who have shown that removal cell suppression in mice, for example, possible on the basis of this and other of Ly-2,3 cell populations (which con is mediated by an antigen-specific T cell work. First, that the I region is func tain suppressor cells) permits the re factor with a molecular weight of about tionally specialised, the 1-J subregion the sidual T cells to collaborate with histo 50,000 and which does not operate being involved in suppression and or T-cell incompatible B cells in the primary across H-2 barriers"·'" (T. Tada, Chiba I-A subregion in macrophage response in vitro to sheep red cells. University). This factor is absorbed by helper functions. Second, the products target cells Independently, Dutton and his col antisera reactive to products of the 1-J of the I region act on controlled by the leagues11 have obtained similar results subregion, which also seems to code for through receptors ·". using anti-Ly antisera and cell separa the receptor for the suppressive factor. same I subregion" M. Taniguchi (Chiba Universi,ty) dis tion techniques, indicating that allo The celJs carrying the receptors (some studies performed with Tada on geneic effects can suppress interactions times known in this context as ac cussed a factor obtained from lysed antigen between histoincompatible T and B ceptors) were found not to be helper primed spleen or thymus cells which cells. Thus, there is no doubt ,that sup T cells, but nylon-wool-adherent T cells augmented lgG antibody responses, pression explains some examples of the which could be killed by anti-1-J serum 10 provided tha.t factor donor and recipient failure of hi,stoincompatible T and B and complement"· • Allotype specific (in culture) were identical in the 1-A cells to interact. Whether all such suppressor T cells can also be killed by region. This factor seems to be different failures can be attributed to suppression antiserum containi,ng antibody to T-J from the helper factor described by is not yet clear. region products••-u (L. Herzenberg © 1976 Nature Publishing Group.

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