Differentiation Arrest of T Lineage Cells in SCID Mice

Abstract

SCID mutant mouse with functional defect of T and B cells is a good model to analyze the developmental mechanism of T and B cells because both lymphocytes do not develop for expressing their functions. It is known that antigen receptors on T and B cells require the gene rearrangement prior to their expression on protein level. Ontogenical studies of normal mouse thymocytes showed that β-chain genes of T cell receptor (TCR) initiate to rearrange in c-kit+ IL-2R+thymocytes but the germ line transcription of these genes occurs at the earlier stage. Since such transcript was not found in non-T cells such as B lymphocytes and kidney tissues. The thymocytes with germ line transcripts are thought to belong to the T cell lineage. In SCID mouse, the process of gene rearrangement is impaired : Southern blot analysis showed that TCR-β genes are not rearranged in SCID thymocytes. However, the germ line transcripts of TCR-β and -α were found in SCID thymocytes. Flowcytometric analysis showed that SCID thymocytes expressed surface markers specific for immature T cells such as Thy-1, Pgp-1 and IL-2 Ra but do not express TCR, CD2, 3, 4 and 8 which are common in mature T cells. These phenotypes were similar to c-kit +CD4-CD8- (DN) embryonic thymocytes which have not yet undergone gene rearrangement of TCR-β and α though these genes were transcribed in germ line. Therefore, it was indicated that SCID thymocytes have already been committed into T cell lineage but their development is arrested at the very early stage. Then, why is the thymocyte development arrested if TCR genes are not rearranged? Recent studies show that development of DN thymocytes into CD4⁺CD8⁺ (DP) thymocytes requires certain signaling by pre-TCR which is a heterodimer composed of pre-TCR-α (pTα) and TCR-β. We found that thymocytes of SCID mouse express pTα but not TCR-β. Thus, it is assumed that SCID thymocytes are not capable of obtaining pre-TCR mediated signal (s) for DN-DP transition. In fact, introduction of a TCR-β transgene into SCID mice induced the generation of DP thymocytes.
These observations indicate that gene rearrangement of TCR-β is essential for T cell development from DN to DP cells as well as TCR protein expression, which was evident in SCID mice.