Abstract
Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations.
Highlights
Age related immune dysfunction includes decreases in generation of naıve CD4 and CD8 T cells, reduced thymic output, narrowing of TCR repertoires, changes in homeostatic proliferation and an accumulation of regulatory T cells [1,2,3,4]
Previous studies of Encephalitozoon cuniculi infection from our laboratory reported a defect in the DC response of 9–12 month old mice, suggesting that immune senescence begins earlier and the accumulating defects can have an impact on control of infectious pathogens as we age [21]
Recent investigations of DC subpopulation biology in response to infectious pathogens have revealed that plasmacytoid DC (pDC) are capable of interacting with conventional DC (cDC) and help them mature resulting in optimal CD8 T cell activation and function [11,33]
Summary
Age related immune dysfunction includes decreases in generation of naıve CD4 and CD8 T cells, reduced thymic output, narrowing of TCR repertoires, changes in homeostatic proliferation and an accumulation of regulatory T cells [1,2,3,4]. Recent studies have demonstrated that innate immunity, which is important for controlling early infection, is defective with age as seen by decreased number and function of macrophages, neutrophils, NK cells and DC [5]. DC responses are down-regulated as a function of age [6,7,8] and since these cells are critical for both innate control of pathogens and the initiation of adaptive immune responses [9], dissecting the mechanisms behind their dysfunction as a result of this phenomenon are essential for adopting novel strategies to boost immunity in the elderly. Previous studies highlight that complex cDC-pDC and cDC-T cell interactions occur and are critical for generation of optimal immune responses [11,12,13]. Whether PD-L1/PD1 interactions between DC subsets play a role in regulation of T cell activation remains unknown
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