Lymphocyte generation and population homeostasis throughout life

Abstract

Immune aging is a multi-faceted process that manifests as reduced competence to fight infections and malignant cells, as well as diminished tissue repair, unprovoked inflammation, and increased autoreactivity. The aging adaptive immune system, with its high complexity in functional cell subpopulations and diversity of B- and T-cell receptors, has to cope with the challenge of maintaining homeostasis while responding to exogenous stimuli and compensating for reduced generative capacity. With thymic involution, naïve T cells begin to function as quasi-stem cells and maintain the compartment through peripheral homeostatic proliferation that shapes the T-cell repertoire through peripheral selection and the activation of differentiation pathways. Similarly, reduced generation of early B-cell progenitors alters the composition of the peripheral B-cell compartment with the emergence of a unique, auto-inflammatory B-cell subset, termed age-associated B cells (ABCs). These changes in T- and B-cell composition and function are core manifestations of immune aging.

Keywords: Age-associated B cells (ABC); B-cell generation; Homeostatic proliferation; Immune aging; T-cell receptor diversity; Thymic involution.

Figure 1. T cell generation and maintenance during aging

The thymus generates novel naïve T cells early in life, providing a diverse T cell receptor (TCR) repertoire. The maintenance of the naïve T cell pool during adult life is entirely dependent on homeostatic proliferation. In old age, aberrant homeostatic proliferation results in contraction of the T cell pool (especially CD8⁺ T cells), decrease in TCR repertoire diversity and generation of virtual memory cells (VM).

Figure 2. B cell generation and maintenance during aging

In older individuals, hematopoietic stem cells (HSC) are skewed towards the myeloid lineage, reducing the number of lymphoid progenitors and subsequently, B cell precursors in the bone marrow. B cell precursors undergo a series of selection events, where initial pre-B cells are positively (+, green bars) selected for functional BCR heavy chain arrangements followed by negative selection (−, red bars) of self-reactive immature B cells, prior to exit from the bone marrow. Once in the periphery, transitional B cells undergo further selection for survival and antigen-specificity. Reduced naïve B cell output from the bone marrow in the elderly leads to memory cell expansion by homeostatic proliferation and contraction of repertoire diversity. In addition, there is accumulation of age-associated B cells (ABCs) and autoreactive antibodies.