Lymphotoxin α1β2: a critical mediator in Vα14i NKT cell differentiation

Lymphotoxin (LT) α1β2, a tumour necrosis factor (TNF) cytokine critically involved in lymphoid organogenesis, is indispensable for the differentiation of Vα14i natural killer T (NKT) cells, a lymphocyte subset with important immunoregulatory properties. However, it is not required for the development of conventional T-cells. LTα1β2 signals through the LTβ receptor, which is expressed on non-lymphoid cells. Triggering of this receptor induces a unique signalling cascade leading to the activation of the transcription factor RelB through activation of NF-κB inducing kinase. This pathway is required for Vα14i NKT cell differentiation as appears from studies in gene-deficient animals. By reciprocal bone marrow chimeras, it was shown that RelB is required in a radiation-resistant host cell or stromal cell for normal Vα14i NKT cell development, presumably in the thymic stroma. These stromal cells are not required for the positive selection of these cells but rather play a prominent role in their terminal differentiation. Altogether, these observations underscore the unique developmental requirements of this particular lymphocyte subset.