Transmembrane control of the receptors on normal and tumor cells: I. Cytoplasmic influence over cell surface components☆

The immunoglobulins which are present on the membrane of B lymphocytes of different species are mobile in the plane of the membrane itself.



This mobility results in the formation of spots of immunoglobulins when the cells are treated with divalent antibodies against immunoglobulins; the spots then combine into polar caps.



The process of spot formation is not inhibited by different substances that inhibit cell metabolism, but is markedly inhibited in the cold.



The formation of caps is followed by the disappearance of immunoglobulins from the cell membrane but, if the cells are not left in contact with the anti-immunoglobulin antiserum, there is a rapid resynthesis of new membrane immunoglobulins. It appears that the percentage of lymphocytes that resynthesize immunoglobulins is identical to that of cells originally carrying immunoglobulins, but the amount of surface immunoglobulins of each cell is increased after antiserum treatment. Many other membrane antigens behave in a similar way after treatment with the corresponding antisera; the possible role of the mobility of membrane proteins for the immunological functions of lymphocytes is discussed.

The dynamic state of the lymphocyte membrane. Factors affecting the distribution and turnover of surface immunoglobulins.

Publisher Summary This chapter describes membrane immunoglobulins and antigen receptors on B and T lymphocytes. There are several qualitative and quantitative distinctions between T-cell and B-cell M-Ig that may explain many of the apparent differences in reactivity of these cells without requiring the existence of a different set of V genes or non-Ig receptors in T cells. Both T and B cells derive from hematopoietic, precursor, stem cells by antigen-independent differentiation. This involves the activation of L-chain and p-type H-chain genes in both cell types. The T-cell and B-cell M-Ig differ primarily in density per cell and possibly in relative exposure on the cell surface with much of the H-chain Fc region inaccessible on T cells. Moreover, the antigen-recognition receptor of both T and B cells involves their M-Ig. On B cells, the receptor is solely the M-Ig, whereas on T cells it is suggested that the specificity of recognition controlled primarily by the M-Ig and binding of antigen to the cell can solely be by the M-Ig receptor. Finally, the activation of the T cell requires an additional interaction of the antigen with another ceIl surface structure that is coded for by a polymorphic H-2 linked gene.

Membrane immunoglobulins and antigen receptors on B and T lymphocytes.

The proteins on surfaces of living splenic lymphocytes from normal BALB/c mice were iodinated enzymatically. Such cells were fractionated into two sub-populations: one composed almost exclusively of small lymphocytes and the other mainly of large lymphocytes and plasma cells. Specific immunoprecipitation of radiolabeled surface Ig obtained from lysates of these cell populations indicated that approximately 2–3% of the acid-precipitable radioactivity from the cell surface is Ig. Moreover, 95% of the H chain radioactivity from the Ig of the small lymphocyte fraction and 90% from the large lymphocyte-plasma cell fraction was characterized as µ by precipitation with anti-µ sera as well as by molecular weight determination on polyacrylamide gels in sodium dodecyl sulfate. The Ig was recovered from the cell surface in the form of an IgM monomer. Control experiments suggested that the monomer did not result from depolymerization of 19S IgM by the methods used to radiolabel and isolate the molecule. 3H-tyrosine labeling of IgM produced by meyloma cells and radio-iodination of IgM in solution gave the same ratios of µL radioactivity as radiolabeling of IgM on cells, indicating that the tyrosine residues of L and µ-chains of cell surface IgM are available to the lactoperoxidase during the iodination. This is consistent with the hypothesis that cell surface IgM is entirely on the outside of the plasma membrane presumably attached to it by its Fc fragment. These results, together with previous reports by others, suggest that IgM, in its monomeric form, is the main antigen-specific receptor on lymphocytes of normal mice.

Cell surface immunoglobulin ii. isolation and characterization of immunoglobulin

One of the motivating forces in lymphocyte biology is the belief that the behaviour of lymphocytes, and more particularly their response to antigen, provides a unique opportunity to analyse the molecular and cellular events involved in the induction and expression of 'differentiation'. A major advance in the realisation of this potential was the finding (Nowell 1960) that quiescent non-dividing small lymphocytes could be triggered into a derepressed state of active growth and proliferation in vitro by phytohaemagglutinin (PHA). The response observed involves parameters common to many systems in which cell growth and proliferation are occurring, e.g. tissue regeneration and embryogenesis, and includes enhanced glycolysis, lysosomal enzyme activity, enhanced nuclear template activity, histone acetylation, DNA polymerase enzyme activity, etc. More specific changes indicative of 'differentiated' activities of lymphocytes, e.g. immunoglobulin synthesis, may also occur, as will be discussed in this review. Although precise quantitation of the number of responding cells has yet to be reported it is clear that the number of cells reacting to PHA and similar stimulants Is considerably greater than one would expect to observe with a classical 'immunological' response in which antigen recognition by relatively small numbers of cells occurs (i.e. 'cional' selection). The response to PHA and other mitogens (see below) is therefore generally considered to be non-specific, i.e. it is a polyclonal lymphocyte response initiated by

Elicitation of selective T and B lymphocyte responses by cell surface binding ligands.

THE initiation of the immune response is believed to involve the recognition of antigen by specific receptors on the surface of lymphocytes. The transformation of rabbit and human lymphocytes by antisera to immunoglobulins1–3, the blocking of antigen binding by lymphocytes using anti-immunoglobulins4 and the inhibition of antigen induced lymphocyte transformation by anti-light chain serum5 suggest that such receptors are immunoglobulin in nature or at least possess immunoglobulin determinants. We have now obtained direct evidence for the presence of immunoglobulin determinants on the surface of rabbit lymphocytes by autoradiography using radio-labelled anti-allotype sera.

Immunoglobulin allotypic determinants on rabbit lymphocytes.

The transformation of rabbit lymphocytes by anti-allotype serum (AAS) has been confirmed. The transformed cells closely resembled at the ultrastructural level those obtained by phytohaemagglutinin stimulation. The cytoplasm contained abundant free ribosomes with virtually no rough surfaced endoplasmic reticulum. A feature peculiar to AAS stimulated cultures was the presence of an amorphous material in and around the blast cells which might represent immune complexes of AAS with its antigen. The suppression of immunoglobulin allotype in animals heterozygous at a given locus by foetal exposure to AAS has been confirmed. It was further shown that this allotypic suppression was accompanied by gross deficiency in the number of peripheral blood lymphocytes which transformed in the presence of the AAS to which the animal had initially been exposed in utero.

Transformation of rabbit lymphocytes by anti-allotype serum: ultrastructure of transformed cells and suppression of responding cells by foetal exposure to anti-allotype serum

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Immunoglobulin allotypic determinants on rabbit lymphocytes.

Transformation of rabbit lymphocytes by anti-allotype serum: ultrastructure of transformed cells and suppression of responding cells by foetal exposure to anti-allotype serum