Saarland University Faculty of Medicine
Biophysik
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Aging of the immune system

The increasing risk of cancer and the severe course of disease associated with infections demonstrate the dramatic impact of immune system impairment on the quality of life and mortality in the elderly. With the rapid increase in the aging population, the compromised immune system with progressive age will become an important public health issue of the 21st century. At cancer diagnosis, the majority of patients are older than 65 years. Yet this age group is often underrepresented in clinical trials of new immunotherapies due to comorbidities and immunosenescence in elderly patients. A better understanding of the underlying mechanism, and the development of new strategies to counteract it, are essential for prolonging healthy life by preventing infectious diseases/cancer and thereby improving the quality of life in later years.

 

 

The research focus of our group is to elucidate cell-intrinsic alterations in the initiation of effector functions of cytotoxic immune cells from humans and mice (CD8+ T cells, NK cells) and their impact on immune competence in aging. In addition to cytotoxic activity against different tumor cells, we are interested in the molecular signaling pathways that control the efficiency of Ca2+-dependent killing of cancer cells. Our previous projects provided some surprising insights into the cell-specific changes of CD8+ T cells in the aging process, which we characterize even further in more detail with a view to immunotherapeutic approaches:

 

Altered Ca2+ signaling in CD8+ T cells from elderly mice

Calcium signals are essential for regulating a broad spectrum of physiological processes. In cells of the immune system, calcium signals are necessary for diverse cellular functions including differentiation, proliferation, effector function, and gene transcription. The major route of calcium influx in human lymphocytes is through store-operated calcium entry (SOCE), mediated by calcium release-activated calcium channels (Icrac). In CD8+ T cells from elderly mice, we demonstrated a reduction in Ca2+ currents through Orai channels due to decreased expression of STIM and Orai proteins and more rapid extrusion of Ca2+ due to increased expression of PMCA4. These changes are associated with reduced CD8+ T cell cytotoxicity sensitivity to variations in external Ca2+ concentration.

 

Increased cytotoxicity of murine CD8+ T cells

Despite reduced Ca2+ signaling and overall reduced T cell immunity with age, the cellular cytotoxic efficiency of CD8+ T cells increases. Using fluorescence-based real-time cytotoxicity assays at the population and single cell level established in our laboratory, we demonstrated that at comparable numbers of cells, CTLs from aged mice exhibit increased cytotoxic activity with enhanced killing kinetics against various tumor cell lines. This heightened cytotoxic efficiency is not limited to specific T cell subtypes. It applies equally to the cytotoxic activity of central memory and effector memory T cells, indicating a broad and robust memory T cell response with age. In addition to in vitro polyclonal stimulation, these results could be confirmed using a newly established heterozygous OT-I aging mouse model. Kinetic analysis of antigen-directed target cell lysis confirmed the high cytotoxic efficiency of CD8+ T cells with age.This dynamic process underscores the potency of these cells in targeting and eliminating potential threats. Increased perforin and granzyme B expression in CD8+ T cells from elderly OT-I mice and C57BL6/J wild-type mice support our hypothesis that cell-intrinsic alterations in the expression of lytic effector molecules drive the augmented cytotoxicity. Furthermore, the high perforin levels in CD8+ T cells from elderly mice shift the mode of target cell death from granzyme-mediated apoptosis to rapid induction of necrosis caused by extensive membrane rupture.