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2.1. A brief overview of T cell development.

T cells develop in the thymus from precursor cells through a series of intermediate stages that can be distinguished based on the expression of marker proteins on the cell surface (Fig. 1)1.

T cell development illustration

Fig. 1. Schematic Illustration of T Cell Development in the Thymus. The different developmental stages encountered by developing T cells can be distinguished based on the expression of cell surface marker proteins that are dynamically up- or downregulated as development proceeds. From early precursors, thymocytes first develop through several substages (DN1-DN4) of the CD4-CD8- double-negative (DN) stage, distinguished via surface expression of CD25 and CD44. At the DN3 stage, DN cells express a pre-TCR composed of a TCRα and a TCRβ subunit. Its surface expression triggers upregulation of CD4 and CD8 on the cell surface and progression into the CD4+CD8+ double positive (DP) stage. DP cells express a mature TCR composed of a TCRalpha and a TCRbeta subunit. At the DP stage, selection processes eliminate non-functional or potentially autoreactive cells through death by neglect or negative selection, respectively. Only cells whose TCR generates appropriate signals are positively selected to survive, downregulate one of the two marker proteins and mature into either CD4 single positive Helper/Regulatory T cells, or into CD8 single positive Cytotoxic T cells. Thymic selection warrants that only T cells with desired functions populate the body. Defects in thymic selection allow malfunctioning T cells or T cells with undesired functions to emerge. This can lead to a variety of severe immune disorders.

Due to the random specificities of their newly generated T cell receptors (TCRs), most of the developing T cells are either non-functional, preventing efficient immune responses, or autoreactive, causing autoimmune diseases if allowed to survive. Such useless or dangerous T cells are eliminated at the DP stage in processes where each T cell's TCR is tested through interactions with thymic antigens. In particular, potentially autoreactive DP cells are induced to die during "negative selection". In a contrasting process termed "positive selection", only T cells with appropriately signaling TCRs are allowed to survive, and induced to differentiate into either CD4+ or CD8+ single positive (SP) mature T cells which then populate the body to defend it against pathogens. CD4-SP cells are key regulators of the immune system. CD8-SP cells have a major function in directly killing pathogen infected cells. Thus, thymic selection at the DP stage is critical for the development of a normal T cell repertoire.

Aberrant thymic selection is one of the main defects causing autoimmune diseases and other disorders of the adaptive immune system. A detailed understanding of the mechanisms governing negative and positive selection is missing, but pivotal for the development of novel therapies for debilitating diseases such as rheumatoid arthritis or asthma. Moreover, the elucidation of the molecular machinery by which TCR signals are split into either negatively or positively selecting signals represents one of the most challenging and fascinating open questions in Immunology.

Further Reading

1. Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu Rev Immunol 21, 139-176 (2003).