Class 11 major histocompatibility complexencoded molecules expressed on the surface of primed B lymphocytes function as restriction elements for presentation of antigen to T lymphocytes, an interaction that ultimately leads to activation and differentiation of both cell types. The engagement of class 11 on a resting B cell, on the other hand, inhibits subsequent B-cell growth and activation. Our studies show that treatment of resting B lymphocytes with anti-class H antibodies, or with other agents (dibutyryl cAMP or isoproterenol) that increase intracellular levels of cAMP, results in the apoptotic death of most or all of the resting B cells. Conversely, treating cells with immobilized anti-immunoglobulin and interleukin 4, conditions known to prime cells, protects them from class 11-mediated death and specifically from increases in nucleosomal fragments characteristic ofapoptotic death. Freshly ex vivo activated B cells likewise are refractory to class 11-mediated apoptosis. Treating B cells with anti-class II reagents causes an elevatidik of cAMP in resting, but not in activated, B cells. These results suggest that apoptotic death is a mechanism of prevention of nonspecific B-cell activation in the event that T-cell receptor and/or CD4 ligation of major histocompatibility complex class 11 occurs in the absence of antigen.One of the paradigms of modem immunology is that major histocompatibility complex-encoded class II molecules bind and present antigenic peptides to helper T cells during an immune response. More recently, there has been a growing acceptance that class II molecules serve at least one additional function-namely, they are signal transducing receptors on the B cells on which they are expressed. Early studies that demonstrated this signaling function in resting B cells involved crosslinking of class II with monoclonal antibodies (mAbs). The ligation of class II on these cells inhibits subsequent mitogenic signals (1) and results in elevated levels of intracellular cyclic adenosine monophosphate (cAMP). In addition, the increases in cAMP result in translocation of protein kinase C from the cytosol to the nucleus (2) but do not cause increases in intracellular calcium or inositol phospholipid turnover (2). Furthermore, increases in cAMP and omithine decarboxylase activity have been observed in resting B cells after direct contact with fixed T-helper cells (3).Recently, many investigators have established the importance of apoptosis, or programmed cell death, as an effective mechanism for the deletion of unwanted cells, specifically lymphocytes, throughout the immune system (4). This form of cell death is characterized by the generation of nucleosome-sized DNA fragments as a result of activation of endogenous endonuclease(s), which cleaves DNA between nucleosomes (4). We propose that in resting B cells, crosslinking of class II molecules results in programmed cell death in these cells and that this mechanism functions to prevent premature class II-mediated activation of B cells that have not b...
The systemic lupus erythematosus-like syndrome in MRL/lpr mice involves high-titered IgG autoantibodies, particularly antinuclear Abs that target histones, DNA, and RNA particles. Although T cell help is required for the generation of antinuclear Abs, the epitopes recognized by such helper T cells are unknown. To address this question, we isolated and sequenced self peptides bound by MHC class II molecules from MRL/lpr mice. We identified a number of peptides that are not seen in similar preparations from nonautoimmune C3H animals. The “abnormal” peptide donors include histone, a protein component of a small nuclear ribonucleoprotein, ribosomal proteins, and RNA processing enzymes. We postulate that the peptides from these donors are T cell epitopes required for the generation of the most frequent antinuclear Abs specificities seen in MRL/lpr mice.
Mouse thymocytes, which are approximately 90% immature cortical cells, are low in surface sialic acid when compared with more mature cortisone-resistant, presumably medullary, thymocytes and peripheral T lymphocytes. Thus, medullary thymocytes bind and are agglutinated by the N-acetylneuraminic acid-specific lectin, lobster agglutinin 1 (LAgl), whereas cortical thymocytes are not agglutinated by this lectin. It is demonstrated herein that mouse cortical thymocytes, purified using LAgl, do not respond to the mitogenic effects of concanavalin A (Con A). The lack of response to this lectin is not due to depletion of macrophages, since addition of macrophages does not restore the response. Populations of LAgl-negative thymocytes can be made to respond weakly to Con A by the addition of interleukin 2, but this response appears to be due to the presence of a few contaminating LAg1-binding thymocytes since it is abolished by treatment of the cells with rabbit anti-LAgl serum plus complement. Therefore highly purified cortical thymocytes not only cannot respond to Con A, but also they cannot be induced to respond by the addition of the T cell growth factor, interleukin 2. Thymocytes isolated by a single criterion, that is by virtue of their low amount of surface sialic acid, appear to be a truly immature population of thymocytes.
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