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Immature B cells that encounter self-antigen are eliminated from the immune repertoire by negative selection. Negative selection has been proposed to take place by two distinct mechanisms: deletion by apoptosis or alteration of the antigen receptor specificity by receptor editing. While convincing evidence exists for each, the two models are inherently contradictory. In this paper, we propose a resolution to this contradiction by demonstrating that the site of first antigen encounter dictates which mechanism of negative selection is utilized. We demonstrate that the bone marrow microenvironment provides signals that block antigen-induced deletion and promote RAG reinduction. In the periphery, the absence of these signals allows the immature B cell to default to apoptosis as a result of BCR engagement.

G protein-coupled receptor inactivation is a crucial feature of cellular signaling systems; this process determines the catalytic lifetime of the activated receptor and is necessary for response termination. Although previous work has indicated a class of models in which several sequential steps are required for receptor inactivation, the rate-limiting event is still unclear. In this paper, we develop a theory that describes the kinetics of inactivation of the G protein-coupled receptor rhodopsin based on the rate of arrestin binding and test the theory using a combination of genetic and electrophysiological techniques in Drosophila photoreceptors. The theory quantitatively describes the inactivation kinetics of activated rhodopsin in vivo and can be independently tested with molecular and spectroscopic data. The results demonstrate that the rate of arrestin binding determines the kinetics of receptor inactivation in vivo and thus is the event that controls signal amplification at the first step of this G protein-coupled transduction cascade.

We have tested several structurally related haptens, conjugated to ovalbumin, for their effect on activation of an inducer T-cell clone reactive to the p-azobenzenearsonate (arsonate) hapten. Low concentrations of some analogs inhibited DNA synthesis and lympkokine production by the clone in response to arsanylated antigen, but not in response to the lectin concanavalin A. Inhibition was specific for this clone, since the response of clones reactive to other antigens was not blocked. Inhibition may result from competition of these analogs with arsonate at a site on the T cell. The effectiveness of blocking by arsonate analogs parallels their ability to bind to a previously described arsonate-binding site on the clone (Rao et al., accompanying paper). We suggest that the binding and blocking assays detect the same physiological arsonate-recognition site on the clone, and hence that the cell-surface arsonate-binding sites we have described mediate its physiological response to antigen.

Inducer T-cell clones reactive to the p-azobenzenearsonate (arsonate) hapten possess binding sites for radioactive arsanylated proteins, which are not present on clones with other antigen specificities. Binding occurred in the absence of histocompatibility proteins. Binding was specific for the p-azobenzenearsonate hapten, since unconjugated proteins and proteins conjugated to the nonactivating o-azobenzenearsonate hapten neither bound to the clones nor competed binding of radioactive antigen. One of the clones was studied in more detail, using a panel of structural analogs of arsonate conjugated to the carrier protein ovalbumin. All conjugates that activated the clone in the presence of antigen-presenting cells also competed binding of radioactive antigen in the absence of antigen-presenting cells. Nonactivating conjugates did not compete binding. Based on evidence in this and the succeeding paper (Rao et al., accompanying paper), we suggest that these arsonate-binding sites may include the physiological antigen receptors of arsonate-reactive T-cell clones.

T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity () provide information about the reciprocal relationship between B cells and Tfh cells. [ABSTRACT FROM AUTHOR]

The reason certain self-antigens are consistently targeted by autoantibodies may be because they are self-adjuvants. Two papers in this issue of Immunity provide important insights into the contribution of Toll-like receptors in systemic autoimmune disease (). [Copyright &y& Elsevier]

provide convincing evidence that liver stellate cells can be antigen-presenting cells. This paper raises the following question: what are the roles and importance of diverse antigen-presenting cells in different organs? [Copyright &y& Elsevier]