Population Size of Innate - like in Regulating the Development and Id 3 and Id 2 Act as a Dual Safety Mechanism

The innate-like T cells expressing Vg1.1 and Vd6.3 represent a unique T cell lineage sharing features with both the gd T and the invariant NKT cells. The population size of Vg1.1 + Vd6.3 + T cells is tightly controlled and usually contributes to a very small proportion of thymic output, but the underlying mechanism remains enigmatic. Deletion of Id3, an inhibitor of E protein transcription factors, can induce an expansion of the Vg1.1 + Vd6.3 + T cell population. This phenotype is much stronger on the C57BL/6 background than on the 129/sv background. Using quantitative trait linkage analysis, we identified Id2, a homolog of Id3, to be the major modifier of Id3 in limiting Vg1.1 + Vd6.3 + T cell expansion. The Vg1.1 + Vd6.3 + phenotype is attributed to an intrinsic weakness of Id2 transcription from Id2 C57BL/6 allele, leading to an overall reduced dosage of Id proteins. However, complete removal of both Id2 and Id3 genes in developing T cells suppressed the expansion of Vg1.1 + Vd6.3 + T cells because of decreased proliferation and increased cell death. We showed that conditional knockout of Id2 alone is sufficient to promote a moderate expansion of gd T cells. These regulatory effects of Id2 and Id3 on Vg1.1 + Vd6.3 + T cells are mediated by titration of E protein activity, because removing one or more copies of E protein genes can restore Vg1.1 + Vd6.3 + T cell expansion in Id2 and Id3 double conditional knockout mice. Our data indicated that Id2 and Id3 collaboratively control survival and expansion of the gd lineage through modulating a proper threshold of E proteins. A subset of T lymphocytes generated in the thymus, gd T cells function between the innate and adaptive immune system. They have features of the adaptive immune system, such as the expression of variable rearranged gd TCRs, but they also have features of the innate immune system, such as the ability to respond to stimulation rapidly (1). They can directly lyse infected or stressed cells, as well as interact with ab T cells, B cells, and dendritic cells, and regulate their functions (2). As a result, gd T cells are involved in a broad range of immune processes, such as infection, inflammation, autoimmunity, tumor surveillance, and tissue maintenance (1, 3). These cells are produced in large numbers in the fetal and neonatal stages in mammals , disseminating and …