Molecular changes associated with ontogeny

There are complex molecular events associated with the development of the B cell lineage consisting of activation or repression of genes encoding cytodiffer-entiation antigens, or activation of genes encoding various receptors associated with the lymphocytic membrane. However, the most important molecular events are related to the expression of immune receptor; namely, the Ig of B cells and the TCR of T cells. The surface Ig of B cells is the product of rearranged V, D, J and C gene segments of heavy chain and V, J, C segments of k and A light chains.

The earliest B cell-specific rearrangement of lg genes occurs in pro-B cells and consists of D—► J,, rearrangement. This process is associated with the activation of recombination activating genes RAG-1 and RAG-2 as well as of terminal deoxyribonucleo-tidyl transferase (TdT) which plays a role in augmentation of diversity by addition of nucleotides during the gene rearrangement process. The activation of these genes leads to the rearrangement of the heavy chain locus and expression of ¡x chain. At this stage, the pro-B cells begin to multiply and differentiate into large pre-B II cells. At this point the RAG genes are downregulated, perhaps in order to achieve allelic exclusion. They are reactivated at the small pre-B II stage to permit the rearrangement of the Ig light chain loci and are then irreversibly shut down when pre-B cells differentiate into immature small lymphocytes.

Following the successful assembly of a complete Ig light chain and its combination with the hcaw chain, a complete IgM antibody molecule appears on the surface of mature B lymphocytes, k light chain loci rearrange before A loci. Successful k gene rearrangement seems to prevent further V gene rearrangement. If k rearrangement is unsuccessful in both alleles. A genes will then recombine.

Mature B cells are characterized by «»expression of surface IgM and IgD. This phenomenon is possible since a single VDJ, associated with two different isotypes, is enabled by differential splicing of inRN'A.

In contrast to B cells which have a single type of immune receptor - namely, immunoglobulin molecules - T cells can express one of two types of receptor: a/ft or y/S. Both of these receptors arc associated with the CD3 molecules, a cytodifferentiation antigen present only on the T cell lineage and which plays a role in the activation of T cells. The a, /3, y, and 8 chains of heterodimeric TCR molecules are encoded by V, J, and C segments similar to Ig molecules, with the ¡3 and 8 chains additionally containing D segments as found in Ig heavy chains.

The y8 bearing T cells are the first to appear in murine fetal thymus, before day 14 of gestation. At this early stage, T cells are Thy-14, CD4" and CD8", and about 5-10% express y8 TCR. The proportion of these cells decreases dramatically after day 16 of gestation to 0.2% in adult thymus. The appearance of y8 cells in thymus is followed by their migration to spleen, epidermis, and intestinal epithelium. There is strong evidence that y8 T cells do not differentiate from a/3 T cells. This is supported in particular by data that show that 8 genes are deleted in a/3 T cells; the location of 8 genes in the a locus results in the deletion of 8 genes during V„-J„ rearrangement.

In ontogeny, the rearrangement of Vp, DJP genes is delayed by 1-2 days and rearrangement of the a locus occurs at a later date. The expression of y8 or a/3 receptor is associated with the synthesis of CD3 antigen; the CD3 gene is probably expressed in pro-thymocytes before the rearrangement of the yd or a/3 genes and before the appearance of the CD4 or CD8 cytodifferentiation antigens.

At the double-negative stage, the cells express RAG genes which generate a functional /3 chain. This event promotes the differentiation of the double negative to the double positive stage, which express low levels of CD3. At the double-positive stage /3 chain is expressed on the surface with pre-a chain. The expression of this pre-TCR signals the progression to the rearrangement of the TCR a locus.

Targeted gene deletion technology allowed the determination of the precise role of several genes in the development of B and T cells. One transcription factor that governs the early commitment of stem cell precursors to the lymphoid lineage is Ikaros. Knockout of the Ikaros gene prevents the appearance of pro-B cells, double-negative T cells as well as natural killer (NK) cells, indicating that the Ikaros gene controls the differentiation of lymphoid lineage precursors from stem cells. The deletion of RAG genes arrests the differentiation of B cells at the pre-B I stage, since no pre-B cells containing ¡x chain are detected in RAG knockout mice. Three other targeted mutations arrest the development of B cells at the same stage. They are inactivation of transcription factors such as Pax-5/BsAP, of A5 and of the Ig £ signal molecules associated with cell surface Ig.

Collectively, these observations show that, in particular, molecular events that concern the genes which encode the immune receptor are associated with various stages of the differentiation of T and B lineages.

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