The unconventional role of LT alpha beta in T cell differentiation.

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