Regulatory T Cell - Development

Development

All T cells come from progenitor cells from the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of T_regs occurs on radio-resistant haemopoietically-derived MHC class II-expressing cells in the medulla or Hassal’s corpuscles in the thymus. At the DP (double-positive) stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become T_reg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional T_regs. T_reg do not have the limited TCR expression of NKT or γδ T cells; T_reg have a larger TCR diversity than effector T cells, biased towards self-peptides.

The process of T_reg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a T_reg is a “Goldilocks” process; T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of T_eff and T_reg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.

Foxp3+ T_reg generation in the thymus is delayed by several days compared to T_eff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. T_reg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3+ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for T_reg functionality, in the thymus, as thymic T_reg from TGF-β insensitive TGFβRII-DN mice are functional.