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Review
. 2014 Sep 15;193(6):2622-9.
doi: 10.4049/jimmunol.1401174.

Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories

Janko Nikolich-Žugich  1
Affiliations
Review

Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories

Janko Nikolich-Žugich. J Immunol. .

Abstract

Until the mid-20th century, infectious diseases were the major cause of morbidity and mortality in humans. Massive vaccination campaigns, antibiotics, antivirals, and advanced public health measures drastically reduced sickness and death from infections in children and younger adults. However, older adults (>65 y of age) remain vulnerable to infections, and infectious diseases remain among the top 5-10 causes of death in this population. The aging of the immune system, often referred to as immune senescence, is the key phenomenon underlying this vulnerability. This review centers on age-related changes in T cells, which are dramatically and reproducibly altered with aging. I discuss changes in T cell production, maintenance, function, and response to latent persistent infection, particularly against CMV, which exerts a profound influence on the aging T cell pool, concluding with a brief list of measures to improve immune function in older adults.

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Figures

Figure 1
Figure 1. Multiple defects in the T cell compartment occur during aging
(Right) T cell development is altered in the bone marrow during aging: the bone marrow stromal changes, as well as cell-intrinsic defects cause hematopoietic stem cells (HSC) and progenitors to shift away from lymphoid and towards myeloid lineages. Thymic T cell development is also altered during aging: there is evidence for decreased seeding from the bone marrow, thymic involution, increased adiposity, and increased expression of proinflammatory cytokines. As a result, the T cell output from the aged thymus is significantly diminished. These developmental defects place stress on peripheral maintenance of T cell pools and T cell function in secondary and tertiary organs (Left). In the peripheral lymphoid organs (spleen and LN) changes in thymic T cell production, along with increased expression of inflammatory cytokines, diminished network of follicular reticular cells and defects in antigen presentation, result in a decrease in the naïve T cell pool, while the virtual memory T cell pool expands (see Fig. 2), hampering responses to new infection. Cell-intrinsic defects as well as impaired Ag processing and presentation synergistically diminish T cell activation, as evident in decreased T cell proliferation and effector molecule expression. Such incompletely or defectively activated effector T cells migrate into tissues (gut, lung, skin, etc.), where decreased effector molecule expression and, potentially, altered trafficking, further contribute to the additive T cell defects with aging, resulting in defective T cell function that limits the response to infection.
Figure 2
Figure 2. Self renewal and differentiation on Naïve CD8+ T cells into phenotypically and functionally distinct CD8 T cell subsets
Their phenotypic attributes, proliferative potential and the functional properties (cytokine production) are illustrated as increased (up arrows ) or decreased (down arrows). Naïve CD8 T cells are maintained by low avidity TCR signaling following pMHC contact and IL-7 (top right). Lymphopenia-driven homeostatic proliferation gives rise to neonatal virtual memory (VM) CD8 T cells (middle right). These VM CD8 T cells can arise early (during the neonatal period) in the thymus (in response to weak TCR signals and IL-4, (37) or in the periphery from the first wave of thymic emigrants, in response to IL-7 (36, 103). Alternatively, over the lifespan, a different type of VM cells can arise in the periphery in response to near-threshold TCR signals that are likely stronger than TCR interactions which maintain naïve T cells in the naïve state (–35, 38). Ligands promoting such VM cells could originate from self antigens or microbiota; these cells accumulate with aging, unlike the neonatal-origin VM cells. Finally, in humans, we recently found a virtually naïve (VN) subset (functionally differentiated yet lacking effector markers) (Pulko, V. et al., in preparation) although it is not yet clear whether such cells are representative of populations generated in the course of antimicrobial responses to foreign antigens or are driven by homeostatic cues.
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