At birth, both the innate and adaptive arms of immunity are functionally incomplete. Newborns depend heavily on maternal antibodies transferred across the placenta for passive protection, and this shield decays within months: estimated durations of maternal antibody protection are roughly 3.3 months for measles, 2.7 months for mumps, 3.9 months for rubella, and 3.4 months for varicella. Neonates can mount adaptive responses, but their capacity to generate long-lasting immunity is limited by underdeveloped germinal centers, low expression of B-cell co-receptors such as CD21, CD40, CD80, and CD86, impaired Th1 cytokine secretion, and reduced B-cell receptor signaling strength. The review emphasizes that this is not simple deficiency. The neonatal immune system operates in a tolerogenic mode, likely to prevent immunopathological damage as the infant transitions from a semi-allogeneic, sterile uterine environment into a microbe-rich world, even at the cost of vulnerability to uncontrolled pathogen proliferation.

The innate immune system, the first line of defense, is active from birth and responds within minutes to hours, but its cellular players mature on very different schedules. Neutrophils appear in fetal circulation by the end of the first trimester and surge before delivery, yet neonatal neutrophils show weak inflammatory responses, a deficit most pronounced in premature infants. Monocytes and macrophages in newborns exhibit diminished signaling and cytokine responses compared with adults, reaching normal levels within days. Crucially, the review highlights the newborn microbiome as the first teacher of the developing immune system: gut microbes induce interleukin-17 production by group 3 innate lymphoid cells, which drives granulocyte colony-stimulating factor release and neutrophil production through a Toll-like receptor 4 and MyD88-dependent pathway, maintaining systemic immune vigilance against infection.

Dendritic cells, the sentinels that bridge innate and adaptive immunity, tell a similarly staged story. Plasmacytoid dendritic cells, the body’s type I interferon factories against viruses, constitute 53 percent of the dendritic cell pool in infants, the lowest total dendritic cell proportion of any age group. Although preterm infants possess adult-like levels of TLR7 and TLR9 on these cells, they secrete low amounts of interferon-alpha and beta, leaving antiviral innate immunity ineffective relative to adults. A progressive increase in conventional dendritic cell subsets occurs during the transition from infancy to childhood, suggesting major immune remodeling early in life. In older adults, the dominant subset is cDC2 at 49 percent, while cDC1 cells expand preferentially in adulthood, possibly compensating for the age-related decline in CD8-positive T cells. Lower plasmacytoid dendritic cell proportions in healthy older people may partly explain their reduced capacity to fight viral infections.

Natural killer cells and other innate lymphoid populations undergo their own lifelong remodeling. Newborn natural killer cells have reduced cytolytic function, blunted sensitivity to interleukin-2 and interleukin-15, and lower interferon-gamma secretion, yet still provide some antiviral protection. During pregnancy, maternal peripheral natural killer cells migrate to the decidua and differentiate into non-cytotoxic cells with enhanced secretory activity, producing interferon-gamma, vascular endothelial growth factor, and placental growth factor that are critical for immune tolerance, angiogenesis, and fetal development, though their hyperactivation can trigger spontaneous abortion. With age, natural killer cells shift toward a mature CD56dimCD16-positive phenotype but become dysfunctional in cytotoxicity, degranulation, and cytokine secretion, weakening the elimination of senescent and malignant cells. Strikingly, single-cell RNA sequencing of three centenarian cohorts revealed increased peripheral natural killer cell frequencies in these exceptionally long-lived individuals, alongside reduced CD4-positive T and B cell counts.

That centenarian signature has crystallized into one of the review’s central themes: cytotoxic immunity as a marker of healthy aging. A bioinformatic algorithm developed to identify immune populations associated with longevity found that natural killer cells, CD8-positive T cells, and gamma-delta T cells correlate positively with extended lifespan, whereas inflammatory-lineage populations such as CD4-positive T cells, B cells, and dendritic cells show negative associations. Centenarian neutrophils display phagocytic and chemotactic activities comparable to those of young adults, with low superoxide anion levels and preserved glutathione, while frail middle-aged subjects show the worst profiles. Reduced complement C3 and C4 levels in centenarians contrast with the elevated levels seen in older adults at risk of metabolic syndrome and cardiovascular disease, and caloric restriction has been shown to downregulate the C3a/C3 ratio, attenuating age-related inflammation. Maintaining cytotoxic phenotypes and redox balance, the authors suggest, may be exploitable clinically to blunt immunosenescence.

The adaptive arm follows an equally dramatic arc. T lymphocytes mature in the thymus from seven to eight weeks of gestation and populate the periphery by weeks twelve to thirteen, but thymic involution drives a progressive loss of naive T cells that accelerates after age sixty. Newborns carry only about 1 percent antigen-educated T cells; in adults over sixty, that figure reaches 65 percent. The T cell receptor repertoire narrows with age, CD28 expression is lost from more than half of CD8-positive T cells, and transcriptional reprogramming pushes aging T cells toward a Th2 polarization associated with dysregulated B cell responses and reduced antibody neutralizing capacity after influenza vaccination, a failure that contributes to influenza deaths in 70 to 85 percent of elderly cases. B cells, meanwhile, peak in the first year of life at around six months before gradually declining, and in old age naive B cells are replaced by quiescent memory cells with diminished affinity maturation and class switching.

Perhaps the most conceptually provocative section concerns immunological memory itself. Long considered the exclusive property of adaptive immunity, memory-like responses have now been demonstrated in innate cells, a phenomenon termed trained immunity. Monocytes, macrophages, natural killer cells, and even bone marrow progenitors exposed to stimuli such as beta-glucan or the Bacillus Calmette-Guerin vaccine undergo epigenetic and metabolic reprogramming that confers enhanced, non-antigen-specific protection against unrelated pathogens for months. In murine models, BCG vaccination at birth improved survival in neonatal sepsis with profound remodeling of monocyte and neutrophil subsets, though some pattern recognition receptor agonists failed to protect neonatal mice against Leptospira, underscoring the risks of immunostimulation in early life. In adults over fifty in Guinea-Bissau, BCG vaccination elevated interferon-gamma and pro-inflammatory cytokine responses two months later, and some reports suggest it can reduce circulating inflammatory markers of inflammaging, although recent large trials found no boost to influenza vaccine responses and even flagged aggravation of cardiac arrhythmias as a concern.

The demographic stakes are considerable. The World Health Organization estimates that people over sixty numbered 1.2 billion in 2025 and will reach 2 billion by 2050, with 80 percent living in developing countries, while the European Union’s elderly share is projected to grow from 6.0 percent in 2021 to 14.6 percent by 2100. Immunosenescence, driven by thymic involution, naive cell depletion, inverted CD4/CD8 ratios, gut microbiota shifts that increase intestinal permeability, and the accumulation of senescent cells secreting interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta, raises vulnerability to infections, cancer, autoimmune disease, and neurodegeneration. Yet the aging immune system paradoxically resembles the newborn’s, with weakened antimicrobial activity and compromised adaptive responses at both ends of life. The Bucharest team argues that mapping these stage-specific mechanisms, from the SOX4-positive naive T cells and interferon-gamma that compensate for infant vulnerability to the cytotoxic dominance that defines centenarian immunity, provides the mechanistic foundation for age-adapted vaccines and immunotherapies capable of restoring immune function in the frail and extending healthy lifespan for everyone else.

Subject of Research: Immune system development across the human lifespan, from neonatal immaturity to immunosenescence and centenarian longevity

Article Title: Immune system ontogeny—a subtle evolution to perfection

Article References: Munteanu, A. N., Surcel, M., Dobre, E. G., Constantin, C., & Neagu, M. (2026). Immune system ontogeny—a subtle evolution to perfection. Frontiers in Aging, 7, Article 1872955. https://doi.org/10.3389/fragi.2026.1872955

Image Credits: AI Generated

DOI: 10.3389/fragi.2026.1872955

Keywords: immunosenescence, inflammaging, trained immunity, neonatal immunity, centenarians, natural killer cells, dendritic cells, T cells, B cells, immunological memory, complement system, BCG vaccine