What the Thymus is Needed for? Intrathymic Events and Their Uniqueness.

In this report we are reviewing principal data on development of T cell lineage in the thymus and some intrathymic factors. The review is concentrated on the main events of T cell intrathymic development and T cell receptor (TCR) formation, thymocyte clone selection and differentiation of T cell subpopulations. Precursor cells migrate into the thymus overcoming hemato-thymic barrier. Once precursor cells have entered "internal space of the thymus" the processes of TCR beta, gamma and delta gene rearrangement are triggered. Then, T precursors choose the particular pathway for further differentiation towards either TCRalpha/beta or TCRgamma/delta bearing cells. Only when cells acquire TCRalpha/beta features they can continue to develop within the thymus, whereas gamma/delta cells emigrate out of it. TCRalpha/beta cells express protoreceptor (complex beta-pre-TCRalpha-CD3) and coreceptors (CD4 and CD8), proliferate and rearrange TCRalpha-chain gene. After TCRalpha-chain gene successful rearrangement the receptor complex TCRalpha/beta-CD3 is expressed on the cell surface. Since the primary antigen-recognizing repertoire contains some useless and harmful (autoreactive) specificities thymocyte population undergo to two-step selection. During the selection clones recognizing any peptides in context of autologous MHC molecules are maintained (positive selection) and those clones recognizing autologous peptides in context of autologous MHC molecules are eliminated (negative selection). At the same time, thymocytes choose between two coreceptor types - CD4 (which has affinity to MHC II) or CD8 (affinity to MHC I). Thymocytes acquiring CD4 coreceptor become precursors helper T cell, and those acquiring CD8 coreceptor differentiate towards cytotoxic T cells. Many of these events are unique, may progress successfully only within the thymus and are managed by factors of thymic microenvironment. The thymic microenvironment includes epithelial and dendritic cells, macrophages, fibroblasts, myeloid and other stromal cells and their products - cytokines, hormones, neuropeptides, molecules of intercellular matrix etc. Each of the intrathymic factors is not thymus specific when considered apart from others, but their combination and spatial organization are unique for this organ and form a kind of "conveyor" which provides optimum conditions for T cell development.