- This page discusses the development and differentiation of T-cells. T-cells develop from Hematopoietic Stem Cells in the bone marrow but the majority of their differentiation occurs in the thymus. An understanding of T-cell Receptor structure may be helpful to understand the following discussion.
|Commitment to T-cell Lineage|
- As mentioned, T-cells develop from Hematopoietic Stem Cells in the bone marrow which can give rise to all blood cells. Commitment to the T-cell lineage first occurs through a lymphocyte progenitor stage which can differentiate into any type of lymphocyte including B-cells, T-cells, or Natural Killer Cells. The precise pathways which give rise to the different types of blood cells is discussed in greater detail in Hematopoiesis. It is thought that certain Lymphocyte Progenitor Cells exit the bone marrow and travel to the thymus where signals are provided that complete the commitment to the T-cell lineage.
- During the thymic stages of T-cell development the cells commit to the T-cell lineage, begin expressing functional T-cell Receptor and T-cell Coreceptor, thus differentiating into CD4+ or CD8+ T-cells. T-cells enter the thymus at its cortex and as they differentiate through the following stages they migrate toward the thymic medulla. During differentiation T-cells are progressively selected for certain properties of their T-cell Receptor. T-cells whose T-cell Receptor does not full-fill certain structural criteria undergo apoptosis. Fully differentiated, mature T-cells at the thymic medulla are then released into the peripheral circulation.
- Double Negative Stage
- Upon entry into the thymus lymphoid progenitors do not express T-cell Receptor or the T-cell Coreceptors, CD4 or CD8, on their surface. Because CD4 and CD8 are not expressed, these cells are referred to as "Double Negative Thymocytes". During this stage, T-cells begin to genetically rearrange and mutate their alpha and beta T-cell Receptor genes. Mutation and rearrangement proceeds through a mechanism highly similar to VDJ recombination during B-cell Development (see page). The end result of these genetic changes are genes which encode a completely unique T-cell Receptor with a unique antigen-specificity.
- Double Positive Stage
- Following successful rearrangement of the TCR genes, T-cells begin expressing the rearranged TCR on their surface along with both the CD4 and CD8 T-cell Coreceptors. Because both CD4 and CD8 are expressed, these cells are termed "Double Positive Thymocytes". During the double positive stage, the T-cells are selected for the capacity of their TCR to recognize host MHC molecules. This "Positive Selection" ensures that any surviving T-cells possess TCRs which can complex with host MHCs, a capacity without which the T-cell could not successfully sample MHC-bound microbial peptides. It is thought that Thymic Epithelial Cells are responsible for presenting MHC to differentiating T-cells in this stage and the next.
- Single Positive Stage
- Following the double positive stage, T-cells lose expression of either CD4 or CD8 and in doing so differentiate into "Single Positive Thymocytes", thus becoming either CD4+ T-cells or CD8+ T-cells. During this single positive stage, the T-cells are selected for those whose TCR cannot recognize host MHC bound to self-peptides. This "Negative Selection" ensures that any surviving T-cells will not be activated by cells that present peptides derived from host molecules. If this negative selection did not occur, host T-cells might mount an immune response against host tissues; indeed, defects in this process may be a cause of Autoimmune Disease.
- Mature T-cells
- The cells which ultimately reach the thymic medulla are CD4+ T-cells or CD8+ T-cells which can bind host MHC but cannot bind host MHC in complex with self-peptide. The positive and negative selective filters described above are thought to eliminate nearly 98% of all T-cells which enter the differentiation pathway. Any T-cells that survive are referred to as naive "Mature T-cells" and are then released into the peripheral blood.
- Naive, Mature T-cells released into the periphery are ready for participation in the Adaptive Immune Response. However, these cells require certain activating stimuli prior to differentiation into effector cells. These activating stimuli are provided by Antigen Presenting Cells and these processes are described more fully in the Adaptive Immune Response.