MHC class II‐dependent T–T interactions create a diverse, functional and immunoregulatory reaction circle

Unlike conventional T cells, innate‐like T cells such as natural killer (NK) T cells are selected by homotypic T‐cell interactions. Recently, a few reports have shown that T–T CD4 + T cells can be generated in a similar manner to that for NKT cells. These two types of cells share common functional properties such as rapid response to antigenic encounters and the potential for a panoply of cytokine secretion. However, T–T CD4 + T cells differ from NKT cells in that they are restricted by highly polymorphic major histocompatibility complex (MHC) II molecules and have a diverse T‐cell receptor repertoire. Additional example of T–T interactions was recently reported in which peripheral T cells re‐circulate to the thymus and participate in the thymocyte selection process. In this review, we dissect the cellular mechanisms underlying the production of T–T CD4 + and NKT cells, with particular emphasis on the differences between these two T‐cell prototypes. Finally, we propose that T–T CD4 + T cells serve two major functions: one as an acute‐phase reactant against viral infection and the other is the generation of anti‐ergotypic CD4 + T cells for regulatory purposes. All of these features make it possible to create a diverse set of functional cells through MHC class II‐restricted T–T interactions.