T cell Development and Regeneration

T cells play essential roles in immune responses. We study how these functional abilities of T cells are acquired during their development. Like other blood cells, T cells originate from blood stem cells resident in the bone marrow. Uniquely among blood cells, their development completes at a distinct anatomical site, the thymus. We're interested in the mechanisms by which some hematopoietic progenitor cells migrate to the thymus. We're further interested in the transcriptional mechanisms in the thymus that direct the earliest thymus colonizing progenitors down the T cell lineage. We hope to understand the regulatory and developmental logic that establishes a functioning immune system.

Current projects in the laboratory include:

1) Migration of hematopoietic progenitors to the thymus. We are studying the signals that permit circulating hematopoietic progenitors to selectively settle within the thymus from the blood, and how these signals change during thymic regeneration. We're interested in whether improved knowledge of thymic homing can be used to enhance migration to the thymus after bone marrow transplantation. (Schwarz and Bhandoola, Nat. Immunol., 2004;  Zlotoff,  et al., Blood, 2010;  Zlotoff,  Zhang, et al., Blood, 2011;  Sultana, et al., J. Immunol., 2012;  Zhang, et al., Blood  2014)

2) Transcription factors that establish and maintain T-cell specific gene expression. TCF-1 and HES-1 are transcription factors that impose T cell identity early in T cell development, but the mechanisms employed are uncertain, and are the focus of intense investigation in our laboratory. We currently think HES-1 represses genes involved in development of non-T cell lineages, whereas TCF-1 may drive T-lineage specific gene expression. We're using conditional alleles of TCF-1 to determine whether TCF-1 controls expression of a common set of T cell genes throughout development, or if TCF-1 instead plays different roles in mature T cells. (Sambandam, et al., Nat. Immunol., 2005;  Weber, Chi, et al., Nature, 2011;  De Obaldia, et al., Blood, 2013;  De Obaldia, et al., Nat. Immunol., 2013)

3) The development and function of innate lymphoid cells. Innate lymphoid cells have transcriptional programs that appear to mirror those of T cells. The comparison of innate lymphocyte cell development with T cell development provides an opportunity to understand the factors that underlie the shared as well as the unique features and functions of these apparently closely related cell lineages. (Yang, et al., J. Immunol., 2011;  Yang, et al., Immunity, 2013)

4) Transcription factors underlying the development, maintenance and regeneration of thymic epithelial cells.

 The Bhandoola Lab, July 2019

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