Neonatal T Cells: A Reinterpretation

Abstract

Neonatal CD4⁺ and CD8⁺ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.

Keywords: CD4+ helper T cells; CD8+ cytotoxic T cells; adaptive immunity; immune development; immunological memory; neonate.

Figure 1

Neonatal and adult T cells have different origins and functions. This figure depicts the layered immune system model for CD4⁺ and CD8⁺ T cells. Unlike adult T cells, neonatal T cells are derived from fetal hematopoietic stem cells, exhibit shorter and more restricted T cell receptors in the absence of TdT, and undergo higher rates of homeostatic proliferation in the periphery. Following stimulation, neonatal T cells more quickly differentiate into effector or regulatory T cells than their adult counterparts, albeit at the expense of forming long-lived memory cells. Abbreviation: TCR, T cell receptor.

Figure 2

Neonatal and adult T cells are programmed differently. This diagram shows how neonatal T cells are transcriptionally shifted to a more effector-like state in early life by developmentally regulated miRNAs. Importantly, these miRNAs (e.g., miR-29, miR-181, and let-7) do not function as on-off switches, but rather as fine-tuners of gene expression in naive CD4⁺ and CD8⁺ T cells at different stages of life. In this way, different miRNAs serve as rheostats for activation (miR-181), effector cell differentiation (miR-29), and metabolism (let-7) in T cells, adjusting various thresholds based upon the need to mount rapid effector or regulatory responses. Abbreviation: TCR, T cell receptor.

Figure 3

Neonatal T cells exhibit innate-like functions. This diagram shows how neonatal T cells express hardwired receptors and display functions that are more typically associated with innate and innate-like T cells. For example, naive neonatal T cells can express Toll-like receptors (TLRs), complement receptors, and natural killer (NK) cell receptors, as well as a more peptide-promiscuous T cell receptor (TCR). Following TCR stimulation, neonatal T cells also rapidly produce IL-8, which is consistent with their more broadly reactive nature. In contrast, adult T cells express a higher avidity TCR and produce more conventional cytokines (IFN-γ or IL-4 and IL-13) after clonal proliferation and differentiation.