Abstract
Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25–29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation.
Highlights
Innate lymphoid cell (ILC) lineages are defined by the expression of key transcription factors and production of cytokines previously associated with T cell lineages
ILCs were identified using sequential gating guided by a previously published protocol [20, 21], with some differences: in our study, anti-CD4 was included in the lineage cocktail, potentially excluding CD4+ ILC1 cells in the analysis and TCRab and TCRgd T cells were not excluded by our lineage cocktail panel
ILC1 cells were the least abundant with ILC3 cells being found at intermediate numbers and frequencies (Figures 1E, F)
Summary
Innate lymphoid cell (ILC) lineages are defined by the expression of key transcription factors and production of cytokines previously associated with T cell lineages. The cytotoxic Group 1 ILC population includes conventional natural killer cells (cNK) and ILC1, while the functions of non-cytotoxic ILC mirror those of CD4+ T helper (Th) cell lineages. Group 1 ILC (ILC1) respond to interleukin-12 (IL-12) and IL-18 to produce interferon-g (IFN-g). Group 2 ILC (ILC2) respond to localized stromal cell (IL-33 and thymic stromal lymphopoietin) or mucosal epithelial cell-derived factors (IL-25) to produce IL-5 and/or IL-13. Group 3 ILC (ILC3) are defined by RORgt and differential expression of NKp44 and either IL-22 or IL-17 with NKp44+ ILC3 being the main producers of IL-22 in tissues [1, 2]
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