Immunotherapy and immunity to cancer: cellular mechanisms.
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Biomedical subjects
Publications and source records attributed to L Moretta.
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Human interleukin-2 (IL-2) is a glycoprotein of relative molecular mass (Mr) 15,000, which is released by T lymphocytes on stimulation with antigen or mitogen and functions as a T-cell growth factor (TCGF) by inducing proliferation of activated T cells. It is generally accepted that resting or activated B cells do not respond directly to IL-2 but require for their proliferation other T-cell-derived lymphokines usually referred to as B-cell growth factors (BCGFs). Recently, however, a monoclonal antibody reacting with the IL-2 receptor molecules expressed by activated T cells (anti-Tac) was shown to react also with certain B tumour cells; in addition, murine B cells proliferate in response to pure human IL-2. We now show that recombinant IL-2, derived from Escherichia coli expressing the human gene, is able to promote strong proliferation of human B cells activated with protein-A-rich Staphylococcus aureus Cowans strain I. Moreover, we demonstrate that the anti-Tac antibody also reacts with S. aureus-activated normal B cells and inhibits sharply the proliferative response of such cells to IL-2. Finally, immunoprecipitation experiments reveal that anti-Tac defines similar molecules on activated T and B cells.
NK cells express receptors characterized by opposite functions that finely regulate their activities. Among inhibitory receptors, some are specific for different groups of MHC class I alleles, while others are still orphan receptors. On the contrary, various activating receptors are involved in the triggering of NK-mediated natural cytotoxicity. In general, their engagement induces human NK cells to kill target cells that are either HLA class I-negative or -deficient. Thus, the process of NK cell triggering mediated by Natural Cytotoxicity Receptors can be mainly considered as a non MHC-restricted mechanism. Here, a brief description of the molecular nature of these receptors, as well as, of their 3D-structures and of the implications for ligand recognition, is given.
Most mature T lymphocytes express CD3-associated antigen receptor molecules (TCR) formed by alpha and beta chains. Recently, a minor subset has been identified that express a different CD3-associated TCR composed of gamma and delta chains. The cell subset expressing TCR gamma/delta differs from conventional T cells in a number of phenotypic and functional characteristics. The simultaneous lack of both CD4 and CD8 antigens at the cell surface allows one to greatly enrich for TCR gamma/delta + cells (by monoclonal antibodies, mAbs and complement). Cloning of CD4-8- peripheral blood lymphocytes revealed that they are homogeneously composed of cytolytic cells which, in most instances, lyse tumor target cells. TCR gamma/delta + cells proliferated in response to allogeneic cells in mixed lymphocyte culture (MLC) and MLC-derived TCR gamma/delta + cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens, thus providing the formal proof that they recognize (allo)antigens. The use of different mAbs specific for TCR gamma/delta molecules allowed us to identify two distinct subsets which bound BB3 and delta-TCS-1 mAbs, respectively. The BB3-reactive molecules in peripheral blood-derived TCR gamma/delta + cells were represented by C gamma 1-encoded disulphide-linked heterodimers, whereas delta-TCS-1 reacted with C gamma 2-encoded non disulphide-linked molecules. Both BB3 and delta-TCS-1 mAb induced activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca++ and/or lymphokine production or cytolytic activity).(ABSTRACT TRUNCATED AT 250 WORDS)
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