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On the Origin and Function of Human NK-like CD8+ T Cells: Charting New Territories

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Human CD8+ T lymphocytes play a pivotal role in maintaining tissue and organ homeostasis. While in circulation between blood-tissues-lymph, CD8+ T cells contact with a variety of cells and factors that play a critical role in modulating and shaping their activation level, their proliferative capacity, and ...

Human CD8+ T lymphocytes play a pivotal role in maintaining tissue and organ homeostasis. While in circulation between blood-tissues-lymph, CD8+ T cells contact with a variety of cells and factors that play a critical role in modulating and shaping their activation level, their proliferative capacity, and their differentiation status; in sum, their functional phenotype. The process of human CD8+ T cell differentiation in the periphery is inexorably linked to loss of CD28 and acquisition of NK and cytokine receptors, among others, and leads to the formation of NK-like CD8+ T cells, also designated as CD8+CD28- T cells, CD8+KIR+ T cells or innate CD8+ T cells. Thus, the appearance of NK-like CD8+ T cells can be envisaged as a necessary step for thymus-derived CD8+ T cells to cope with the internal changes caused by a variety of stimuli both TCR-dependent and TCR-independent. Although in terms of TCR repertoire human NK-like CD8+ T cells are mostly oligoclonal, in functional terms they are polyfunctional, which may explain the divergent observations regarding their proliferative potential, cytokine secretion and cytotoxic versus regulatory function. It is now becoming evident that NK-like CD8+ T cell responsiveness to MHC-I-peptide mediated signals has been downplayed while receptiveness to other signals, such as cytokines, growth factors, and damage associated factors, has been upregulated. Due to their polyfunctional phenotype, NK-like CD8+ T cells populating or circulating through the different tissues and organs are in a privileged position to control basic physiological processes, from cell-mediated removal of damaged, anomalous or infected cells by phagocytic cells to tissue remodeling and repair by stromal cells.

A deeper understanding of the signals activated by environmental factors that drive NK-like CD8+ T cells formation and maintenance within a number of peripheral tissues and organs should provide novel insights into the biological implications of the phenotypic and functional changes that occur during CD8+ T cell lifetime in humans.

From a pathological point of view, a variety of environmental cells (e.g., epithelial, endothelial, mesenchymal, neuroglia, etc.) and factors (e.g. cytokines, hormones, neurotransmitters, cell metabolites, nutrients, contaminants, or pathogenic antigens) are known to shape human CD8+ T cell differentiation and function and have been associated with immune deregulation, chronic inflammation and cognitive impairment in a variety of human diseases, including autoimmunity, cancer, cardiovascular disease, respiratory diseases and neurodegeneration. However, many questions remain to be elucidated, for example how, when and why otherwise harmless environmental factors become harmful/inflammatory? Does the phenotype of NK-like CD8+ T cells change according to the factors present within a particular microenvironment? What is the role of the immune-non-immune cells crosstalk within the environment? Last, but not least, what is the response of the NK-like CD8+ T cells to these changes?

In this Research Topic we encourage submission of original research articles, reviews, perspectives, or methods addressing the study of tissue/organ cells (e.g., epithelial cells, endothelial cells, mesenchymal, neuroglia, etc.) and/or factors (e.g., cytokines, hormones, peptides, neurotransmitters, etc.) on the generation of human NK-like CD8+ T cells, including but not limited to activation, proliferation and survival pathways, epigenetics of receptor expression, and effector/regulatory functions. Considering the impact of NK-like CD8+ T cells on health and disease, we aim to provide a range of articles summarizing the current knowledge on the mechanisms that regulate their formation and shape their function.


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