Negative selection of lymphocytes

Almost by definition, negative selection of T and B lymphocytes cannot be absolute. Given that both sets of receptors are derived by stochastic processes, recognition of epitopes by lymphocyte receptors will not be an all or none affair but a relative one. Too effective a mechanism of negative selection would have resulted in deletion of the whole repertoire, as all specificities would have cross-reacted with some self-epitope at least to some degree. This review has documented some of the influences impacting on emerging T and B cell repertoires that result in a removal of the most dangerous self-reactive cells and the progressive quantitative and qualitative increase, through positive clonal selection, of other cells specific for the actual foreign antigens encountered by each individual. T and B lymphocytes pass through a stage where their natural reaction to antigen is one of negative selection and on to a later stage where the cell is more likely to become activated. Geography plays a role in this; the primary lymphoid organs are designed largely to exclude foreign antigens and to present self-antigens, whereas the secondary lymphoid organs are designed to filter out and concentrate foreign material and to promote costimulatory intercellular immune interactions. Ontogeny of individual cells also plays its role, probably through the progressive assembly of the full receptor signaling machinery, incomplete arrays promoting a negative rather than a positive signal. However, the differing susceptibilities of immature and mature cells to silencing by deletion or anergy are relative rather than absolute. Negative signaling may involve immediate or somewhat delayed death of the anti-self-cell, and in some cases the bad cell may have the chance of editing its receptor to create one lacking anti-self-reactivity. Alternatively, the cell may receive a nonlethal down-regulatory signal and may be induced into a state of anergy. Such anergic cells may have a reduced life span, showing that anergy and deletion may shade into each other. Upon the removal of antigen (an unlikely event for cells anergic to an authentic self-antigen), the state of anergy is reversible. The strength of the receptor cross-linking signal may chiefly determine whether deletion (strong cross-linking) or anergy (weaker cross-linking) supervenes. Some lymphocytes with self-reactivity ignore the self-antigen in question because of low affinity, poor accessibility, lack of suitable presentation, or absence of appropriate help.(ABSTRACT TRUNCATED AT 400 WORDS)