Extrathymic T cells stand at an intermediate phylogenetic position between natural killer cells and thymus-derived T cells.

A series of recent studies have revealed that extrathymic pathways of T cell differentiation exist at multiple sites in mice and humans. In terms of their properties, extrathymic T cells may stand at an intermediate position between natural killer (NK) cells and thymus-derived T cells in phylogenetic development. It is speculated that primitive lymphocytes such as NK cells and extrathymic T cells develop from primordial macrophages in intraepithelial regions of e.g., the intestine, skin and liver. In this regard, the immune system of the bone marrow and thymus is relatively recent, developing after the emergence of living beings onto the land (i.e., amphibia). A complete elimination of self-reactive T cell clones occurs in mainstream intrathymic T cell differentiation and a consistent generation of such clones occurs through the extrathymic pathways. Therefore, thymus-derived T cells are efficient for processing foreign antigens, whereas extrathymic T cells recognize abnormal self-cells. Although thymus-derived T cells play the major role in youth, extrathymic T cells may play rather a pivotal role with aging and under conditions of malignancy, intracellular infections, pregnancy, and autoimmune diseases.