The immuno-cognitive crossfire: redefining age-related T and B cell dynamics as drivers of neurodegeneration and systemic inflammaging

Abstract

Aging of the adaptive immune system is not a uniform decline but a patterned reorganization of T and B cell compartments that can drive both systemic inflammaging and neurodegeneration. This review synthesizes emerging evidence that CD8 + CD28− EMRA cells, regulatory T cell instability, Th17 drift, age-associated B cells (ABCs), and ectopic meningeal lymphoid structures collectively form an immuno-cognitive axis linking peripheral immune aging to central nervous system pathology. We propose that clonal hematopoiesis (CHIP), rheumatoid arthritis-associated inflammation, and statin-sensitive immune trafficking represent a systemic-chronic inflammatory continuum that precedes and shapes proteinopathy. Therapeutically, senolytics (dasatinib + quercetin), BAFF-R antagonists, CAR-Tregs engineered for CNS antigens, and checkpoint modulation offer distinct but complementary strategies to break this crossfire. We introduce the term Adaptive Immuno-Senescent Pathology (AISP) to replace the imprecise label “immunosenescence,” emphasizing tissue-specific, functionally consequential immune remodeling. A translational architecture is proposed combining longitudinal TCR-seq, cognitive endpoints, and hippocampal volumetry to establish causality rather than correlation. This framework redefines age-related T and B cell dynamics as actionable drivers rather than passive bystanders of neurodegeneration. The immuno-cognitive crossfire: adaptive immune remodeling as a bridge between systemic aging and neurodegeneration. Healthy aging is supported by sustained thymic output, a diverse T-cell receptor repertoire, stable regulatory T cells, and balanced B-cell homeostasis, whereas advancing age progressively reorganizes adaptive immunity through thymic involution, repertoire contraction and clonal expansion of CD8⁺CD28⁻ EMRA cells, Treg instability, Th17 polarization, and expansion of age-associated B cells (ABCs). These peripheral changes converge at the brain-border interface, the choroid plexus, meninges, and blood–brain barrier, where CXCL10–CXCR3, CCL20–CCR6, and BAFF/BAFF-R signaling can promote lymphocyte recruitment, retention, and survival. Loss of immune-barrier homeostasis facilitates FcγR-dependent microglial activation, inflammasome and oxidative signaling, and downstream tau hyperphosphorylation, amyloid-β pathology, white-matter injury, synaptic loss, and cognitive decline. In parallel, clonal hematopoiesis, chronic systemic inflammatory states, endothelial dysfunction, and myeloid skewing reinforce a bidirectional vicious cycle in which peripheral inflammation primes the CNS and neuroinflammatory responses further sustain systemic inflammaging. The framework termed Adaptive Immuno-Senescent Pathology (AISP) therefore conceptualizes immune aging not as uniform immune failure, but as tissue-specific and functionally consequential remodeling that may provide measurable biomarkers and therapeutic entry points. Emerging strategies—including senolytics, BAFF-R antagonism, CNS-directed CAR-Tregs, and carefully controlled checkpoint modulation—illustrate potential approaches for disrupting this immuno-cognitive crossfire, while emphasizing that several interventions remain preclinical or mechanistically unresolved.