Id3 and Id2 collaboratively regulate innate-like γδ T cell development (HEM3P.275)

Abstract

Abstract γδ T cells expressing the Vγ1.1 and Vδ6.3 TCR chains are one of growing numbers of recently characterized innate-like lymphocytes. Id3 has been shown to be a major transcription regulator to prevent the development and expansion of this population. We showed that deletion of Id3 resulted in a dramatic expansion of Vγ1.1Vδ6.3 T cells on the C57BL/6 background. This phenotype is in contrast to the much milder phenotype when the Id3 mutation was initially characterized on the 129/sv background. We conducted a quantitative trait analysis in search of the presumed Id3 modifier(s). Id2 was mapped as a major modifier of Id3 in suppressing Vγ1.1Vδ6.3 cell expansion. This mapping result was further confirmed by introduction of the targeted allele of Id2 to the Id3 mutant background. Our study led to four major observations: first, a decrease in Id2 expression on Id3 deficiency background promotes expansion of Vγ1.1Vδ6.3 cells. Second, complete elimination of both Id2 and Id3 genes triggers apoptosis instead of further expansion of Vγ1.1Vδ6.3 cells. Third, Id3 and Id2 collaboratively control survival and expansion of the γδ lineage through regulating a proper threshold of E proteins. Finally, Id proteins seem to control cell survival and expansion post Vγ1.1Vδ6.3 lineage specification. Based on these findings, we propose a dual safety mechanism to explain the role of Id3 and Id2 in regulating the population size of Vγ1.1Vδ6.3 T cells.