The CD8+ T cell response to intracellular pathogens such as bacteria, viruses and protozoan parasites is an essential component of host resistance. This proposal utilizes experimental infectious disease models of bacteria, Listeria monocytongenes, and Vaccinia virus to address questions about the host CD8+ T cell immune response against potential microbial agents of bioterrorism. We have discovered that E protein transcription factors and their inhibitor, Id2, regulate the CD8+ T cell response to intracellular pathogens, which is a novel function for these proteins. It is our goal to understand at a molecular level how this family of transcriptional regulators influences the activation, proliferation, differentiation and survival of CD8+ T cells as they transition from naove to effector to memory cells. While the E proteins are known to regulate many key developmental check-points, lineage commitment, proliferation and survival during hematopoiesis and lymphocyte development, the function of these important proteins is unexplored in the mature T cell. We hypothesize that the activation of CD8+ T cells and subsequent generation of memory cells during the immune response involves the regulation of E protein- transcriptional targets. To gain insight into the specific E protein-transcription factors that regulate gene expression, the genes which are regulated by their activity during the CD8+ T cell response and how the inhibition of their activity regulates memory T cell formation, we propose to:
Aim 1 : Determine which E proteins regulate the in vivo CD8+ T cell response. We will examine the immune response by E2A, E2-2 and HEB-deficient T cells and the DNA-binding activity of each of these proteins during infection with Listeria monocytogenes and Vaccinia virus.
Aim 2 : Identify the molecular pathways controlled by E protein-transcription factors during the in vivo CD8+ T cell immune response to infection.
Aim 3 : Create an Id2-reporter mouse line to define the Id2 expression pattern during the immune response and determine if Id2 expressing effector T cells are the precursors to memory T cells.
|D'Cruz, Louise M; Stradner, Martin H; Yang, Cliff Y et al. (2014) E and Id proteins influence invariant NKT cell sublineage differentiation and proliferation. J Immunol 192:2227-36|
|Best, J Adam; Blair, David A; Knell, Jamie et al. (2013) Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat Immunol 14:404-12|
|Knell, Jamie; Best, J Adam; Lind, Nicholas A et al. (2013) Id2 influences differentiation of killer cell lectin-like receptor G1(hi) short-lived CD8+ effector T cells. J Immunol 190:1501-9|
|Omilusik, Kyla D; Shaw, Laura A; Goldrath, Ananda W (2013) Remembering one's ID/E-ntity: E/ID protein regulation of T cell memory. Curr Opin Immunol 25:660-6|
|D'Cruz, Louise M; Yang, Cliff Y; Goldrath, Ananda W (2010) Transcriptional regulation of NKT cell development and homeostasis. Curr Opin Immunol 22:199-205|
|D'Cruz, Louise M; Knell, Jamie; Fujimoto, Jessica K et al. (2010) An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells. Nat Immunol 11:240-9|
|D'Cruz, Louise M; Rubinstein, Mark P; Goldrath, Ananda W (2009) Surviving the crash: transitioning from effector to memory CD8+ T cell. Semin Immunol 21:92-8|