Human T Cell Development, Localization, and Function throughout Life

Abstract

Throughout life, T cells coordinate multiple aspects of adaptive immunity, including responses to pathogens, allergens, and tumors. In mouse models, the role of T cells is studied in the context of a specific type of pathogen, antigen, or disease condition over a limited time frame, whereas in humans, T cells control multiple insults simultaneously throughout the body and maintain immune homeostasis over decades. In this review, we discuss how human T cells develop and provide essential immune protection at different life stages and highlight tissue localization and subset delineation as key determinants of the T cell functional role in immune responses. We also discuss how anatomic compartments undergo distinct age-associated changes in T cell subset composition and function over a lifetime. It is important to consider age and tissue influences on human T cells when developing targeted strategies to modulate T cell-mediated immunity in vaccines and immunotherapies.

Keywords: T cell subset; development; human immunology; memory; memory T cells; mucosal immunity; thymus.

Figure 1. Overview of changing role of T cells in at distinct life stages

In early years, when humans encounter many antigens for the first time, T cells mediate pathogen clearance for multiple acute infections, develop memory responses, and establish tolerance to innocuous foreign antigens. After childhood, the T cell compartment is more stable with fewer acute infections and reduced generation of memory. During many decades of adult life, T cells maintain homeostasis in tissues by controlling chronic infections, surveilling for cancer cells, and maintaining proper immunoregulation. Finally, in advanced age there is a well-documented decline in T cell function and a corresponding increased susceptibility to infection, cancer, and autoimmunity.

Figure 2. Defining features of human Trm cells

Trm cells have a unique profile of transcription factor expression, surface expression of homing receptors and adhesion markers to maintain tissue residency, and a distinct functional profile with increased expression and ability to secrete both pro and anti-inflammatory cytokines. Trm cells also upregulate a number of inhibitory genes and exhibit reduced proliferative turnover compared to circulating memory T cell counterparts.

Figure 3. Distinct changes in human T cell subsets with age in diverse tissue sites

The T cell compartment in humans undergoes major changes from infancy to old age, with key differences by tissue site. Thymic output declines from a very early age and by middle adulthood there is negligible thymic output as measured by peripheral TREC content or DP thymocytes. After early childhood, the relative contribution of the thymus to the peripheral pool of naïve T cells is low due to peripheral mechanisms for naïve T cell maintenance. In all tissues, there is a shift from naïve to memory predominance that occurs with this transition observed during childhood in barrier tissues such as lung and intestines with only very low levels of naïve T cells persisting in adulthood, and much later in adult years in lymphoid sites with lymph nodes exhibiting the slowest transition to memory T cell predominance. Resident memory T cells comprise a varying fraction of the memory compartment in tissues (highest in barrier tissues, lower in lymph nodes); however, the development of Trm cells lags slightly behind the development of memory. Terminally differentiated T cells that re-express CD45RA (Temra) comprise an important fraction of CD8⁺ T cells in blood, spleen, and lungs, with increased frequencies in old age and with CMV infection.