The unconventional role of LTαβ in T cell differentiation

Lymphotoxin (LT)αβ, a member of the tumor necrosis factor cytokine superfamily, and its receptor, the LTβ receptor (LTβR), have a well defined role in secondary lymphoid organogenesis but an unexpected function in T cell differentiation. Although earlier studies indicated that conventional T cell subsets were normal in mice deficient in the LTβR pathway, accumulating evidence indicates that the LTαβ–LTβR pathway has a pivotal role in the ontogeny of unconventional T cells, including γδ T cells and invariant natural killer T cells. The LTβR pathway seems to operate at distinct levels during thymic development. Double positive thymocytes regulate the differentiation of early thymocyte progenitors and γδ T cells through a mechanism dependent on LTβR. In addition, LTβR signaling in thymic stroma was proposed to affect central tolerance to peripherally restricted antigens. These findings highlight the complex cellular crosstalk between lymphoid and stromal compartments during thymic differentiation.