Dual T cell receptor beta chain expression on human T lymphocytes.

Abstract

Slltmmsr~Allelic exclusion of lymphocyte antigen receptor chains has been hypothesized as a mechanism developed by the immune system to ensure efficient lymphocyte repertoire selection and tight control of lymphocyte specificity. It was effectively shown to be operative for both the immunoglobulin (Ig) and the T cell receptor (TCR) B chain genes. Our present observations suggest that close to 1% of human T lymphocytes escape this allelic control, and express two surface TCK B chains with distinct superantigenic reactivities. Since this high frequency of dual ~ chain expressors did not result in any dramatic immune dysregulations, these results question the need for a mechanism ensuring clonal monospecificity through allelic exclusion.T mphocyte antigen receptors are composed of two vari-1./ able glycoprotein subunits, the Ig heavy and light chains on B cells and the TCK ot and/3 or y and ~ chains on T cells. The genes coding for Ig and TCK chains are formed through somatic rearrangement of V, D, and J elements (for reviews see references I and 2). Given its diploid nature, any lymphocyte clone could theoretically express up to four distinct combinations of antigen receptor chains on its surface. Since donal plurispecificity, possibly resulting from expression of multiple antigen receptors on the same cell, is expected to lead to immune dysregulations (that is, autoimmunity), control processes ensuring allelic exclusion of antigen receptor chains were postulated more than a decade ago, and their existence demonstrated through elegant Ig and TCK transgenic mouse models (3-5).More recently it has become clear that the stringency of aUelic exclusion greatly differs from one antigen receptor chain gene to another. In the case of TCK/~ chain genes, expression of any productively rearranged gene prevents further rearrangement in the B locus, a process referred to as "genotypic" exclusion (6). Such a genotypic control is illustrated by the arrest of endogenous TCR B gene rearrangements in mice carrying a functional or truncated B transgene (5, 7). However, similar transgenic studies have failed to demonstrate a dramatic influence of functional ol transgenes on the occurrence of rearrangements within endogenous TCK o~ loci (8-12). Moreover, studies performed on normal T cells have revealed the expression of distinct productive cz transcripts (13) or even distinct surface cz chains (14) on a fraction of murine and human T cell clones.Although lack of aUelic exclusion of ol chains can result in a violation of the "one cell, one receptor" rule, current ontogenic models suggest that dual ol chain expression would have limited physiological consequences. Experiments with normal and transgenic T cells suggest that a developing lymphocyte will keep on rearranging its ot loci until it produces a TCR o~ chain able to pair with the available TCK ~ chain and form a TCK showing sufficient affinity for selfMHC-peptide complexes (12,13,15). The corollary to this hypothesis, which proposes a close coupling between arrest of TCK cz gene...

Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

“…In a similar manner, also 1% of T cells do not follow the rule of allelic exclusion, but express two different alleles of T-cell receptor beta-chain. The consequent change in the avidity of the expressed T-cell receptors may allow these cells to escape negative selection in the thymus and/or their expansion in the periphery [33,34].…”

Allelic Exclusion at the TCRδ Locus and Commitment to γδ Lineage: Different Modalities Apply to Distinct Human γδ Subsets

“…This mechanism of allelic exclusion has been thought to be the process responsible for the maintenance of clonal distribution of B and T cell Ag receptors. The observation that a functional ␣ rearrangement occurs on each allele in a large percentage of the T lymphocyte population and that the ␤ locus escapes from allelic exclusion, leading to the expression of two surface TCR, however, called into question the necessity of maintaining monospecificity (5,6). Allelic exclusion then rather seemed to be the consequence of a particular mode of rearrangement arrest than an active monospecificity control mechanism.…”

HLA class I‐restricted recognition of an HIV‐derived epitope peptide by a human T cell receptor α chain having a Vδ1 variable segment

“…Despite the allelic exclusion system operating on TCR genes, as many as 30 and 1% of human peripheral § g T cells have been reported to coexpress two different § or g chains on their surface, respectively [11][12][13]. In addition, +ˇT cells expressing two different + orˇchains have also been reported [14][15][16].…”