MULTIPLE REARRANGEMENTS IN T-CELL RECEPTOR ALPHA-CHAIN GENES MAXIMIZETHE PRODUCTION OF USEFUL THYMOCYTES

Peripheral T lymphocytes each express surface T cell receptor (TCR) al pha and beta chains of a single specificity. These are produced after random somatic rearrangements in TCR alpha and beta germline genes. Pu blished model systems using mice expressing TCR alpha and/or beta chai n transgenes have shown that allelic exclusion occurs conventionally f or TCR-beta. TCR alpha chain expression, however, appears to be less s trictly regulated, as endogenous TCR alpha chains are often found in a ssociation with transgenic TCR beta chains in TCR alpha/beta transgeni c mice. This finding, coupled with the unique structure of the TCR alp ha locus, has led to the suggestion that unlike TCR beta and immunoglo bulin heavy chain genes, TCR alpha genes may make multiple rearrangeme nts on each chromosome. In the current study, we demonstrate that the majority of TCR-, noncycling thymocytes spontaneously acquire surface expression of CD3/TCR. Further, we show that cultured immature thymocy tes originally expressing specific TCR alpha and beta chains may lose surface expression of the original TCR alpha, but not beta chains. The se data provide evidence that not only must multiple rearrangements oc cur, but that TCR alpha gene rearrangement continues even after surfac e expression of a TCR alpha/beta heterodimer, apparently until the rec ombination process is halted by positive selection, or the cell dies. Sequential rearrangement of TCR alpha chain genes facilitates enhanced production of useful thymocytes, by increasing the frequency of produ ction of both in-frame rearrangements and positively selectable TCR al pha/beta heterodimers.