Maturation and function of natural killer cells during aging

Current population aging is without parallel in human history and it brings significant socio-economic and political challenges with it. The immune system is profoundly affected during aging, a process termed immunosenescence. A hallmark of aging is the increased susceptibility to infections and cancer. Since Natural Killer (NK) cells play a critical role in immune-surveillance against virally-infected and transformed cells, a clearer understanding of the key players in NK cell maturation might help to better design innovative therapeutic strategies relevant to aging and other conditions of persistent immune activation, such as chronic infections and cancer. The aim of this thesis is to detail the age-associated alterations in human and murine NK cell subset repartition, maturation, phenotype, transcriptional regulation and effector functions. We compared the phenotype and function of human NK cell subtypes using three models of persistent immune activation: aging, cytomegalovirus (CMV) infection and hepato-cellular carcinoma (HCC). This study established that CD57, NKG2C and TIM-3 were hallmarks of NK cell immunosenescence and that acquisition of these markers correlated with CMV and inflammation status of the donors. Mature NK cells gained poly-functionality but lost cytotoxicity potential in older donors and their functionality was, at least partially, regulated by the TIM-3/Ceacam-1 pathway. Also, work demonstrated that HCC progression was associated with tumor infiltration of exhausted and cytotoxic-deficient NK cells expressing CD57, TIM-3 and Ceacam-1. Clinical stages of HCC could be segregated according to co-expression of Ceacam-1 and TIM-3. Moreover, we sought to expand the knowledge on how aging impacts NK cell differentiation and function in murine models, such as C57BL/6 wild-type mice and Timp-3 KO mice. We demonstrated that, in aged C57BL/6 wild-type mice and aged Timp-3 KO mice, NK cells are reduced in frequency and numbers and exhibit an altered phenotype in the blood and spleen. Investigating the expression of a variety of cell surface markers associated with the maturation process, we showed that aging is characterized by an accumulation of immature NK cells coupled with a reduction in the late differentiated subset. This phenotypic immaturity reflected a relevant functional immaturity. Our results showed that cytokine secretion, cytotoxicity and gene expression of NK cells are modulated by the aging process along a maturation pathway defined by CD11b and CD27 and, in some cases, LY49H and KLRG1. In particular, NK and T cells from older Timp-3 KO mice experienced the same qualitative age-related changes as the lymphocytes from the wild-type counterparts; however, the kinetic of these changes was accelerated in old Timp-3 KO animals, resulting in earlier NK and T cell immunosenescence. These data offer new insights into TIMP-3 biological role in adaptive and innate immunity, especially its importance during the aging process. This project deepened our understanding of human and murine NK cell differentiation and functionality during aging, leading to novel insights into age-related dysfunctions in NK cell responses and innate immunosenescence. Our findings could support the identification of new immunological targets for checkpoint blockade therapies in order to rescue early innate defense upon aging, chronic infections and cancer.