The unconventional role of LTαβ in T cell differentiation

Lymphotoxin (LT)alpha ss, a member of the tumor necrosis factor cytokine superfamily, and its receptor, the LT ss receptor (LT ss R), 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 LT ss R pathway, accumulating evidence indicates that the LT alpha ss-LT ss R pathway has a pivotal role in the ontogeny of unconventional T cells, including gamma delta T cells and invariant natural killer T cells. The LT ss R pathway seems to operate at distinct levels during thymic development. Double positive thymocytes regulate the differentiation of early thymocyte progenitors and gamma delta T cells through a mechanism dependent on LT ss R. In addition, LT ss R 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.