Age-associated remodeling of T cell immunity and metabolism

Abstract

Aging results in remodeling of T cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T cell metabolism, with a focus on the bioenergetic and immunologic features of T cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental for the development of therapeutic strategies for older patients.

Keywords: T cells; aging; cancer; immunity; immunotherapy; metabolism; mitochondria.

Figure 1:. A brief overview of T cell development and activation.

T cell development begins in the bone marrow with hematopoietic stem cells that acquire a lymphoid progenitor state. These cells migrate to the thymus, a specialized primary lymphoid organ, to undergo additional maturation and selection against self-reactive T cell clones. During this process, progenitor T cells differentiate into either mature CD4⁺ or CD8⁺ T cells and exit the thymus. These antigen-naive T cells can be activated in the lymph node by dendritic cells which provide TCR, co-stimulatory and cytokine signaling for the acquisition of effector T cell functions.

Figure 2:. Naïve T cells from aged hosts display attenuated glycolysis and mitochondrial metabolism.

Aged naïve T cells display defective TCR signaling (a), early metabolic activities (including glycolysis and pentose phosphate pathway) (b), and transcriptional and proteomic reprogramming required for mitochondrial biogenesis (c).

Figure 3:. Reconfiguration of T cell subtypes with aging.

A. Aging is associated reconfiguration of immune cell types in the periphery, including the expansion of myeloid cells, decreased proportions of naïve CD8⁺ T cells, and accumulation of unique age-related T cell types. B. Aged naïve T cells undergo defective catabolic and anabolic metabolism upon TCR-stimulation, resulting in decreased functional effector and memory T cells. C. Trajectory of naïve T cells in aged hosts. As a result of cell-intrinsic and environmental perturbations, naïve T cells differentiate and expand into age-related T cell populations: CD8⁺CD28⁻ T cells, terminally differentiated effector memory T cells re-expressing CD45RA (Temra), age-associated T (Taa) cells and virtual memory T (Tvm) cells have been reported to expand with aging and display distinct immune and metabolic signatures.

Figure 4:. Age-associated changes in anti-tumor T cell immunity and response to ICB.

Aging results in systemic remodeling of primary, secondary lymphoid tissues, and the tumor microenvironment, all of which have significant implications for anti-tumor T cell immunity and ICB. Increased myelopoiesis plays a central role in shaping the immunosuppressive environment in secondary lymphoid and tumor tissue, whereas thymic involution and defective T cell development limit TCR diversity and naïve T cells required for anti-tumor immunity. The literature suggests defective T cell priming and anti-tumor T cell responses occur with age. Furthermore, aging is associated with an increased pool of PD-1⁺ T cells and expression of PD-L1/PD-L2 on APCs. However, the overall response to ICB remains unclear, and may be context-dependent.