Editors' ChoiceImmunology

A New Innate Cell on the Block

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Science Translational Medicine  08 Oct 2014:
Vol. 6, Issue 257, pp. 257ec174
DOI: 10.1126/scitranslmed.3010423

The intestine serves as a bouncer for the body, allowing entry to materials that we want (such as food) and restricting others to behind the velvet rope (such as commensal bacteria). A single cell layer of epithelium is all that stands in the way of the undesirables, which although potentially beneficial in the intestinal lumen could wreck havoc if allowed entry into the body tissues. Fortunately, the epithelial cells have backup: Interspersed within the epithelial cells are a variety of immune cells, including intra-epithelial lymphocytes (IELs), which are primarily composed of adaptive immune cells such as gamma-delta and CD8α+ T cells. Although CD8α has long been studied as a co-receptor for T cell activation, it has recently become appreciated that there is a population of CD8α+ cells that lack a T cell receptor. However, the characterization and function of these cells has remained elusive.

A recent report by Van Kaer et al. has uncovered a role for these cells in the maintenance of intestinal health. The authors began by characterizing these cells in mice, examining surface markers that are commonly expressed on a variety of immune cells. Interestingly, they identified that these cells expressed markers associated with myeloid cells—part of the innate immune system—but lacked expression of markers that belong to the newly identified population of innate lymphoid cells (ILCs). Microscopic analysis revealed that these cells were in intimate contact with the epithelium and physically looked much like a lymphocyte. The presence of these cells was exclusive to the intestine, indicating that these cells may be a gut-restricted cell type that possesses properties belonging to both innate and adaptive immunity. Based on this, the authors name these cells iCD8α cells for innate CD8α cells.

Transcriptional profiling revealed that iCD8α cells expressed a set of genes that included granzymes, genes associated with phagocytosis, and osteopontin, the wound healing cytokine, an expression profile distinct from other cells. Because iCD8α cells are closely associated with the intestinal epithelium, the authors hypothesized that they might function to defend the intestinal mucosa. They first demonstrated that iCD8α cells could phagocytose live bacteria and process and present antigen. Animals that were genetically modified to have fewer iCD8α cells had worsened intestinal disease when infected with an invasive Escherichia coli, demonstrating the importance of this cell type for gut defense. The authors also isolated iCD8α cells from human intestine and identified a severe depletion of these cells in newborns with necrotizing enterocolitis, providing compelling evidence that iCD8α are an innate-like cell type that promotes human intestinal health.

The intestine contains the largest environmentally exposed surface area on our bodies, and it is likely that sophisticated mechanisms have evolved to tolerate food and commensal bacteria while mounting effective immunity against pathogens. Several previously uncharacterized cell types have been identified within the intestine over the past decade that possess qualities belonging to both lymphoid and myeloid lineages. The identification of iCD8a cells suggests that the intestine is home to a plethora of cells that have yet to be discovered and identify the need to better characterize the complex cellular environment that help promote human intestinal health.

L. Van Kaer et. al., CD8αα+ innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity 41, 451–464 (2014). [Abstract]

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