Alternative processing of RNA in lymphoid cells

Abstract

In a recent paper Zamoyska etal. ~ have shown that there are at least two messenger (m)RNA species in thymocytes for the Lyt 2 cell surface marker antigen of mouse cytotoxic/suppressor cells (the equivalent antigen is CD8 in humans and MRC OX-8 in rats). The two mRNA species differ in that one has a 31 base pair deletion in the sequence coding for the cytoplasmic region which, with the shift in reading frame, results in a cytoplasmic tail of only 3 amino acids compared to 28 in the larger form. This provides a molecular explanation for the observation that two polypeptide chains c~ and c~' of the Lyt 2 antigen are found on thymocytes and is consistent with the biochemical studies of Luscher eta/. 2 which suggest that the smaller e' form, differs only in having a shorter cytoplasmic tail. Given the lack of understanding of the role of cytoplasmic tails of membrane glycoproteins in general, the functional significance of this is unclear. However, it is possible that the shorter form (c~') is not important in T-cell function as it and its mRNA are present in much lower amounts in mature T cells ~. Zamoyska et al. showed that the two mRNA species for Lyt 2 are derived from a single gene by alternative splicing at the RNA level 1. Mammalian genes are subdivided into exons which contain the coding and untranslated regions found in mRNA and these are separated by intervening sequences - introns. Both exons and introns are transcribed into a large nuclear RNA transcript and then the introns are spliced out to give the mature mRNA containing contiguous coding sequence, which is then translated in the cytoplasm. Introns vary greatly in size from about 50 to 10 000 or more base pairs but the positions of their boundaries with exons have characteristic sequences at which precise splicing occurs to give an mRNA containing all the required exons 3. However, alternative splicing can occur so that during the splicing event exons may be spliced out together with the introns resulting in a different protein product. This is what appears to happen in the Lyt 2 case described above, and many other examples of alternative splicing have been described in a number of tissues 4-6. One of the best examples is that of immunoglobulin heavy chains. B lymphocytes can express both IgM and IgD simultaneously at the cell surface. The initial RNA transcript runs from the leader and the rearranged V domain exons (V-D-J) through the C domain exons for both i and 6 chains 7-9. This is processed to give the V domain together with either the I~ or 6 C domains, i.e. to