Building a T cell compartment: how immune cell development shapes function

Abstract

We are just beginning to understand the diversity of the peripheral T cell compartment, which arises from the specialization of different T cell subsets and the plasticity of individual naive T cells to adopt different fates. Although the progeny of a single T cell can differentiate into many phenotypes following infection, individual T cells are biased towards particular phenotypes. These biases are typically ascribed to random factors that occur during and after antigenic stimulation. However, the T cell compartment does not remain static with age, and shifting immune challenges during ontogeny give rise to T cells with distinct functional properties. Here, we argue that the developmental history of naive T cells creates a 'hidden layer' of diversity that persists into adulthood. Insight into this diversity can provide a new perspective on immunity and immunotherapy across the lifespan.

Fig. 1 |. Immune challenges and solutions during development.

a | Development from fetal life to adulthood requires progressive adaptation to environmental and infectious challenges. Prenatal life is characterized by the need for tolerance and the absence of infectious threats. Once born, an animal must cope with exposure to a diversity of novel antigens, learn to differentiate pathogenic colonization from commensal colonization and develop an effective memory response to common pathogens. b | The host adapts to these various immune challenges by alternating haematopoietic stem cell origins, changing the duration of post-thymic maturation, changing T cell receptor (TCR) diversity and varying the amounts of homeostatic proliferation. c | The interplay of specific challenges and solutions results in age-related biases in signal responsiveness and commitment to effector or memory fates. RTE, recent thymic emigrant; TdT, terminal deoxynucleotidyltransferase; T_reg cell, regulatory T cell.

Fig. 2 |. Naive T cell subsets differ in their ability to respond to antigens and inflammation.

Immune challenges elicit a spectrum of responses from developmentally distinct subsets. Cells made early in life are more responsive to inflammatory signals and undergo rapid proliferation and differentiation. This allows rapid effector responses but is detrimental for the generation of robust memory. By contrast, cell subsets generated in adulthood respond to low levels of an antigen and make strong memory responses but require a significant time to become functional. RTEs, recent thymic emigrants.

Fig. 3 |. Evolution and adaptation of the T cell compartment with progressing age.

The composition of the pool of naive T cells changes over time owing to changes in stem cell origin, T cell production, post-thymic T cell differentiation and survival. In infancy, the peripheral T cell pool is dominated by neonatal recent thymic emigrants (RTEs), which progressively differentiate to neonatal phenotype mature naive (MN) cells and virtual memory (VM) cells as a result of homeostatic proliferation. In time, these are complemented by the arrival of adult RTEs, which also differentiate over time into MN cells and VM cells, albeit at a slower rate than in infancy. At any given age, the composition of the responding naive T cell pool is unique and leads to changes in how the pool responds to novel infections. Shortly after birth, the response is dominated by fast-esponding, inflammation-sensitive subsets. Through infancy, fast-responding neonatal cells persist to provide protection, while newly arrived adult subsets begin to establish high-avidity immunological memory. In adulthood, the highly antigen-sensitive adult-derived subsets are mostly highly represented, leading to slower responses but enhanced memory formation. Perturbations in normal immune development due to infection, malnutrition or environmental factors can perturb the T cell pool, resulting in it containing higher or lower levels of neonatal immune cells.