CDI Lab, HMH Specialists Identify Vital Pathway Initiating Cellular Immunity in Science Immunology Journal

A researcher at the Hackensack Meridian Center for Discovery and Innovation (CDI) and physician-scientist colleagues from Hackensack Meridian Health have shown how a critical pathway is fundamental to the immune system.

The results by Hai-Hui “Howard” Xue, Ph.D., and colleagues are published in the latest edition of Science Immunology - and could have implications in cancer immunotherapy and vaccine developments for years to come.

Establishing cellular immunity depends on the thymus, a lymph gland located in front of the heart. This gland produces and exports T cells, a workhorse white blood cell, out to the rest of the body, using the building blocks of stem cells from the bone marrow. But it has remained a riddle how T cell fate is initiated.

The new paper shows that two protein “transcription factors” called Tcf1 and Lef1 are critical modulators that direct bone marrow stem cells to the T cell path in the thymus.

By carefully removing these proteins via in vivo and ex vivo models, the team of scientists revealed a foundational event in the immune system, which represents essentially the very origin of a functional cellular immune competence.

This discovery illustrates a whole new understanding of T cell formation, and could lead to a wide range of novel approaches in treating immune deficiencies, autoimmune diseases, and optimizing immunotherapies in the ongoing fight against cancer.

“These findings reveal that Tcf1 and Lef1 act much earlier than previously recognized, extending beyond their roles in promoting T-cell lineage specification and commitment at later stages in the thymus,” the authors write, adding that the “downstream” Notch signalling pathway is corrupted without these two assisting proteins.

“In summary, our systematic analyses identify Tcf1 and Lef1 as pivotal regulators of the inception of T lineage potential at the pre-thymic stage,” the authors add. “Although expressed at low levels, they have an indispensable role in enabling hematopoietic progenitors to respond to Notch signaling prior to seeding the thymus.”

This latest work involved collaborators from several domestic and international academic institutes, including the University of Virginia, Henry Ford Health System in Michigan, and universities in the Shanxi and Zhejiang provinces in China, as well as two colleagues at the CDI: Johannes Zakrzewski, M.D., and Rachel Rosenstein, M.D., Ph.D.

Xue’s previous work has focused on Tcf1, Lef1, and their extended partners in CCD8+ T cell biology. Tcf1 essentially "preprograms" a particular type of memory CD8+ T cells, called T central memory (Tcm) cells, preparing them to respond quickly and robustly to threats, i.e., pathogens that the immune system has seen before, according to previous papers by Xue and his team.

Tcf1 is what Xue has additionally called a “core regulatory circuit” for almost all T cell functional aspects. While it is known for its predominant regulatory functions relating to different T cells, Tcf1’s role includes: promoting the self-renewal of stem-like CD8+ T cells generated in response to viral or tumor antigens, which could boost checkpoint blockade immunotherapy for cancer; differentiating follicular helper and T follicular regulatory cells in helper T cells; crucially regulating immunosuppressive functions of regulatory T cells; and functioning as the first transcription factor to show the capacity to bridge transcriptional and epigenetic regulation.

Xue’s other recent publications have shown ways that this pathway could potentially be modulated to produce more effective vaccines by taking the natural “brakes” off the immune system, and also to better treat chronic and acute myeloid leukemia.

“We are fortunate to have been studying one of the most important regulators of T-cell immunity during the past decade,” Xue said recently. “Since our initial publication in Immunity in 2010 on the function of TCF1 in mature T cell responses, there has been exponentially increased interest and knowledge in this molecule in various T cell subtypes.”