Deletion of factors in the Id3 pathway results in a dramatic phenotype where Vγ1Vδ6.3 (γδ NKT) T cells become the dominant T lymphocyte (113.2)

Abstract

Abstract Recent work from our lab and others has shown a significant expansion of γδ NKT cells in mice that lack the HLH-protein Id3. In contrast to WT mice, nearly all Id3-deficient γδ NKT cells express high levels of the innate T cell determinant, PLZF and produce copious amounts of IL-4 upon activation. We have been exploring the transcriptional network that controls the development of γδ NKT cells. In an effort to identify additional factors that play a key role in expansion of γδ NKT cells, we have undertaken a candidate approach to evaluate genes that function in the Id3 pathway. To do this we are studying single and double gene deficient mice to determine the interrelation of different transcription factors. These studies have led to the discovery of a gene combination that results in a dramatic alteration of thymopoiesis. In these mice, while thymic cellularity was not affected, the frequency of γδ T cells versus αβ T cells was reversed. γδ T cells were found to be the dominant lymphocyte, representing ~65% of the cells. Furthermore, nearly all of the γδ T cells were now found to express PLZF. This dramatic phenotype appears to be T cell-specific, as both myeloid and lymphoid lineages are present. Analysis of thymic progenitors revealed major alterations in DN2-DN4 stages of development. Our findings uncover a fundamental regulatory pathway that favors the development of γδ NKT cells, while restricting the maturation of pro-T cells into the conventional T cell lineage.