NK Cells in the Human Lungs

Abstract

The lung offers one of the largest exchange surfaces of the individual with the elements of the environment. As a place of important interactions between self and non-self, the lung is richly endowed in various immune cells. As such, lung natural killer (NK) cells play major effector and immunoregulatory roles to ensure self-integrity. A better understanding of their abilities in health and diseases has been made possible over the past decade thanks to tremendous discoveries in humans and animals. By precisely distinguishing the different NK cell subsets and dissecting the ontogeny and differentiation of NK cells, both blood and tissue-resident NK populations now appear to be much more pleiotropic than previously thought. In light of these recent findings in healthy individuals, this review describes the different lung NK cell populations quantitatively, qualitatively, phenotypically, and functionally. Their identification, immunological diversity, and adaptive capacities are also addressed. For each of these elements, the impact of the mutual interactions of lung NK cells with environmental and microenvironmental factors are questioned in terms of functionality, competence, and adaptive capacities. As pulmonary diseases are major causes of morbidity and mortality worldwide, special attention is also given to the involvement of lung NK cells in various diseases, including infectious, inflammatory, autoimmune, and neoplastic lung diseases. In addition to providing a comprehensive overview of lung NK cell biology, this review also provides insight into the potential of NK cell immunotherapy and the development of targeted biologics.

Keywords: CD103; CD49a; NK cells; lung; tissue-resident NK cells.

Figure 1

Lung NK cell subpopulations. Like peripheral blood NK cells, lung NK cells represent 20% of all the Lymphocytes and are composed of three different subsets: CD56^dimCD16⁺, CD56^dimCD16⁻, and CD56^brightCD16⁻ NK cells. Each subset expresses three markers of residency differentially. As a result, most of the lung NK cells do not express these markers: they form the circulating NK cells. They belong to the CD56^dimCD16⁺ population and disclosed a terminally differentiated phenotype. In contrast, the cells expressing CD69, CD49a, and/or CD103 are considered as being resident NK cells. Almost all of them are CD56^brightCD16⁻ or in a lesser extend CD56^dimCD16⁻ NK cells. They display a less mature phenotype. Among them, triple positive CD49a⁺CD69⁺CD103⁺ are thought to be more specifically the resident population, representing in fine < 3% of the total lung NK cells.

Figure 2

Example of flow cytometry data illustrating the subset of resident lung NK cells. Flow cytometry analyses were performed on BALF in a patient with severe interstitial lung disease. The expression of the cell surface markers was performed after gating on CD3⁻CD56⁺ NK cells. (A) Proportions of CD56^dim/bright and CD16^+/− NK cells. (B) High expression of CD69⁺ on NK cells. (C) Proportions of resident NK cells according to CD103 and CD49a expression. The proportion of resident lung NK cells was higher than expected on normal lung samples. Numbers represent the % of the different populations.