?? T cells represent a unique group of lymphocytes arising from the same thymic progenitors that also produce ?? T cells. Although these two groups of T cells are closely linked in development, they clearly play distinct roles in the immune system. In contrast to ?? T cells, which require help from innate immune cells, many ?? T cells appear to function as the first line of defense and can provide immediate responses to pathogens by secreting cytokines and chemokines. In this regard, ?? T cells perform important innate immune functions to help control infections and to facilitate the induction of adaptive immune responses. Thus far we know little, about the regulatory mechanisms that control the developmental timing and effector fates of individual functional groups of ?? T cells. Id3, a small nuclear protein, has been shown to play differential roles in lineage differentiation among different groups of ?? T cells. Id3 exerts its regulatory role by inhibiting the E-protein family of transcription factors, notably E2A and HEB, which directly regulate many lineage differentiation (c)vents including rearrangement and expression of the TCR ? and 5 genes. Although the importance of Id3 in regulating E-protein function during ?? lineage specification has been clearly established, the dynamic changes of downstream transcriptional networks are still poorly defined. We propose to use genetic means to distinguish the functions of Id3 at different stages and in different lineages of T cell development. In particular, the assessment of Id3-mediated pathways will be facilitated by genetic analysis involving the combination of conditional Id3, Id2, E2A, and HEB alleles. We will use this newly established genetic system to determine the mechanisms by which ld3 controls lineage choice between ?? and ?? T cell fate and lineage choice between different subtypes of ?? T cells. This genetic approach will be conducted in conjunction with the other three related projects included in this program project grant Together, we seek a comprehensive understanding of molecular pathways underlying ?? lineage choice and specification of effector function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Fahl, Shawn P; Coffey, Francis; Kain, Lisa et al. (2018) Role of a selecting ligand in shaping the murine ??-TCR repertoire. Proc Natl Acad Sci U S A 115:1889-1894
Zarin, Payam; In, Tracy Sh; Chen, Edward Ly et al. (2018) Integration of T-cell receptor, Notch and cytokine signals programs mouse ?? T-cell effector differentiation. Immunol Cell Biol 96:994-1007
Zhang, Baojun; Jiao, Anjun; Dai, Meifang et al. (2018) Id3 Restricts ?? NKT Cell Expansion by Controlling Egr2 and c-Myc Activity. J Immunol 201:1452-1459
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Chisolm, Danielle A; Savic, Daniel; Moore, Amanda J et al. (2017) CCCTC-Binding Factor Translates Interleukin 2- and ?-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs. Immunity 47:251-267.e7
Li, Jia; Roy, Sumedha; Kim, Young-Mi et al. (2017) Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors. J Immunol 198:3136-3148
Zhu, Yina; Gong, Ke; Denholtz, Matthew et al. (2017) Comprehensive characterization of neutrophil genome topology. Genes Dev 31:141-153
Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Kenian et al. (2017) The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development. Immunity 46:818-834.e4
Moore, Amanda J; In, Tracy Sh; Trotman-Grant, Ashton et al. (2017) A key role for IL-7R in the generation of microenvironments required for thymic dendritic cells. Immunol Cell Biol 95:933-942

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