A Possible Cause Identified for the Decline in Natural Killer Cells in Old Mice

The aging immune system becomes dysfunctional and inefficient for a number of reasons, such as too many cells in its limited repertoire becoming specialized memory cells, leaving too little capacity for the killer T cells responsible for destroying pathogens. That is a problem of the adaptive immune system, but the innate immune system has its own distinct issues. The innate immune cells analogous to killer T cells are known as natural killer (NK) cells; their numbers and functionality decline with aging, making the innate immune response ever less effective. In the research quoted below researchers are coming close enough to root causes for natural killer cell dysfunction to begin attempting interventions aimed at specific cellular mechanisms, though as yet without success:

While it is now well established that in mice and humans NK cells become dysfunctional with age, the whole scope of the dysfunctions and the underlying mechanisms remain unknown. Here, we characterized the impairment of NK cells of aged mice to a greater extent than before, demonstrated that the origin of the defect is in the stroma of the bone marrow. We have previously reported a decreased number of total NK cells in the blood and spleen and reduced frequencies of mature NK cells in the blood, spleen, lymph nodes, and bone marrow of aged mice. Here, we expanded this finding by demonstrating that immature NK cells in the aged mice proliferate poorly, have additional characteristics of immature cells including decreased KLRG1 and increased CXCR3 expression, and dysregulated expression of Eomes and several inhibitory and activating receptors. Expression of activating and inhibitory receptors was also altered with aging, but the reason and functional consequences of these changes remain to be elucidated.

Our analysis of mixed bone marrow chimeras showed that the deficiencies of the NK cells in aged mice are not due to intrinsic defects of the hematopoietic precursors but due to an inadequate stroma. A characteristic of aging is the decline of lymphopoiesis and an increase in myelopoiesis. The main mesenchymal cell types in the bone marrow that regulate hematopoiesis are osteoblasts and adipocytes. Osteoblasts are essential for lymphopoiesis, while bone marrow adipocytes are known to suppress lymphopoiesis and promote myelopoiesis. Moreover, a deficit in osteoblasts results in decreased numbers of hematopoietic stem cells in the bone marrow. Increased bone marrow adipogenesis and decreased proliferation and maintenance of osteoblasts are characteristics of aging.

Our data show that developmental defects in NK cells of the aged are due to deficiencies in the mesenchymal stromal cells of bone marrow but not due to the hematopoietic stem cells. These defects are the consequence of deficient maturational cues provided by bone marrow stromal cells. Notably, the mesenchymal stromal cells are responsible for the production of type I and type IV collagen in the bone marrow. Our data showed that NK cells in aged mice have low expression of α2β1 (CD49b CD29) integrin, receptor for type I collagen with reciprocal increases in expression of α1β1 (CD49a CD29) integrin, and receptor for type IV collagen. Whether these findings are causally related and whether the interaction of developing NK cells with collagen in the bone marrow is required for proper NK cell maturation need to be further explored.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12291/


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