Figure 1.

Regulatory CD4⁺ cells can develop in a number of ways, although the mechanisms by which these occur and the relationship of the resulting cells to one another are contestable. Thymically generated Treg cells, otherwise known as natural T_R cells or CD25⁺CD4⁺ T_R cells, develop intrathymically according to a specialized combination of TCR and costimulatory signals. Extrathymically generated T_R cells, e.g., Tr1 cells or Th3 cells, can be generated under a whole host of conditions. Whether a conventional naive CD4⁺ T cell can be converted in the periphery to a de facto Foxp3⁺ T_R cell remains controversial.