T-cell antigen-receptor genes in autoimmune mice

Abstract

The developmental patterns of rearrangement and expression of the T-cell antigen-receptor genes are precisely regulated during T-cell differentiation and education. The beta- and gamma-subunit RNAs of the T-cell receptor are abundantly expressed in immature thymocytes. In mature thymocytes the alpha- and beta-subunit RNAs are preferentially expressed, whereas there is minimal expression of the gamma RNA. Although aspects of the pattern of known organization and rearrangement of the T-cell receptor gene in the thymus have been studied and the concept of a thymus selection process generally has been accepted, the cellular and molecular basis of thymus education remains obscure. Certain strains of mice with predilections for autoimmunity demonstrate T-cell developmental abnormalities. This is especially true for the lpr/lpr or gld/gld genotypes, in which the major population of peripheral T cells is developmentally disturbed. We have studied the development, expression, and rearrangement of T-cell receptor genes in the C3H/HeJ gld/gld mouse. Our results indicate a high level of expression of the beta and alpha RNAs in C3H/HeJ gld/gld T cells residing in the periphery. In addition, the beta-subunit gene of gld/gld peripheral T cells undergoes more rearrangements than does its normal C3H/HeJ T-cell counterparts. We speculate that this rearrangement pattern and high level of T-cell receptor mRNA reflects an abnormality or deficit in a thymus selection process that permits emigration of T cells with nonfunctionally rearranged T-cell receptor genes to secondary lymphoid organs. However, the normal level of gamma-subunit RNA expression argues that gamma-subunit gene rearrangements are distinct from processes related to alpha- and beta-subunit selection.