2025-09-24 イェール大学
(Illustration by Michael S. Helfenbein)
<関連情報>
- https://news.yale.edu/2025/09/24/primed-and-ready-how-one-fast-acting-type-white-blood-cell-fights-infection-infants
- https://www.pnas.org/doi/10.1073/pnas.2421106122
初期のヒトCD8 + T細胞は、急速で短命なエフェクター応答と独特な転写因子ランドスケープを示す Early-life human CD8+ T cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape
Nina N. Brodsky, Monisha Chakder, Dinesh Babu Uthaya Kumar, +7 , and Carrie L. Lucas
Proceedings of the National Academy of Sciences July 28, 2025
DOI:https://doi.org/10.1073/pnas.2421106122
Significance
During the trajectory from fetal to neonatal to infant life, naive CD8+ T cells are developmentally tuned through incompletely understood mechanisms. Here, we report that naïve neonatal human CD8+ T cells are poised for an immediate effector switch within hours of activation, including significantly increased glycolytic capacity, proliferation and cell death, differentiation, and production of effector molecules such as TNFα. Coupled with the distinctive transcriptomes of naïve neonatal CD8+ T cells is a unique set of transcription factors they express, which includes elevated TOX and HELIOS in both the resting and activated states. These distinctive features persist into infancy, underscoring their potential implications for shaping early-life responses to infections and vaccination while avoiding tissue immunopathology.
Abstract
Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8+ T cells displaying innate-like characteristics and a low threshold for T cell receptor activation. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize avoidance of tissue immunopathology, especially while maternal immunoglobulin provides passive immunity. We set out to define the unique response characteristics and transcription factor landscape of neonatal human CD8+ T cells. Here, we report evidence that naïve neonatal human CD8+ T cells are poised for an accelerated effector switch, with elevations of killer cell lectin-like receptor G1 (KLRG1), killer cell lectin-like receptor B1 (KLRB1/CD161), Fc epsilon receptor I-gamma (FCER1G), DNAX accessory molecule-1 (DNAM1/CD226), granzymes, tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), and glycolysis compared to naïve adult CD8+ T cells. Further, rapid proliferation and cell death occur upon activation of neonatal CD8+ T cells, with cell viability largely rescued by IL-2 or IL-7. These features are coupled with a unique transcription factor landscape, including high expression of thymocyte selection associated high mobility group box (TOX) and HELIOS (IKZF2), and these signatures continue in postnatal life until at least 2 mo of age. We conclude that early-life human CD8+ T cells maintain a unique transcriptional state associated with an accelerated effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.
