Abstract
Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC have long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naïve peripheral T cells. Zfx-deficient T cells also failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell compartment was severely reduced. RNA-Seq analysis revealed that the most dysregulated genes in Zfx-deficient T cells were similar to those observed in Zfx-deficient HSC and B cells. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion and highlight the common molecular basis of HSC and lymphocyte homeostasis.
Highlights
A hallmark of acquired immunity is the ability to mount a highly specific response to a wide variety of foreign antigens
The peripheral T cell compartment consists of quiescent “naïve” cells that are characterized by surface expression of CD62L, “activated” cells that express CD44 in response to external stimulating signals [such as antigen or cytokines released in response to lymphopenia [43]], and “memory phenotype” cells that have completed homeostatic proliferation and express both CD62L and CD44
At 12 months of age, there was a distinct population of CD8+CD62L+CD44+ cells in the Conditional knockout (CKO) mice, which represent “memory phenotype” cells that have undergone homeostatic proliferation in response to lymphopenia [7, 8]
Summary
A hallmark of acquired immunity is the ability to mount a highly specific response to a wide variety of foreign antigens. Central to this process is a tightly regulated, complex program of T cell homeostasis that involves coordination of cell survival, expansion, differentiation, and death in a number of different contexts. A variety of regulatory mechanisms ensure that the appropriate rare T cell responds to an antigen and maintains a memory of antigen exposure, while the remaining T cell pool actively represses both inappropriate hyperactivation as well as death while maintaining a diverse T cell compartment for the entire life of the organism. Over the life of an organism, naïve T cells are continuously lost due to cell death, differentiation, and migration. Mathematical modeling and experimental data have revealed that, as an organism ages and
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