A serum-marker-based framework for inferring CD4+T-cell lineage shifts: introducing the tpi model in atherosclerosis

Abstract

Atherosclerosis (AS) is a chronic disease in which immune responses are key drivers of pathogenesis. Among immune cell populations implicated in AS, CD4+T cells are closely associated with both systemic and lesional inflammatory activity. Changes in their lineage states are key factors in sustaining inflammation,and promoting plaque progression. The upstream and downstream pathways that regulate CD4+T-cell lineages are relatively well defined, and their regulatory mechanisms are understandable. Here, we define CD4+T-cell lineage deviation as an imbalance between pro-inflammatory (Th1/Th17) and regulatory (Treg) states; the magnitude of this deviation is associated with AS progression. In AS, deviation typically manifests as a Th1/Th17-skewed inflammatory state accompanied by inadequate Treg-mediated regulation. However, there is still no analytical framework that effectively integrates peripheral serum markers, immune signaling pathways, and CD4+T-cell lineage states, which limits our understanding of how systemic metabolic and inflammatory cues shape immune dysfunction during disease progression.

In recent years, growing evidence has shown that commonly used clinical serum markers, including LDL, HDL, HbA1c, C-reactive protein (CRP), and creatinine, are not merely metabolic indicators but reflect systemic lipid-related risk, inflammatory status,and organ function. Through pathways such as NF-kB, STAT3, mTOR, AhR, and LXR, these signals collectively shape CD4+T-cell lineage bias toward Th1, Th17, or Treg states, supporting the use of peripheral serum markers to infer inflammation-related immune deviation.

On this basis, we propose the T-cell Perturbation Index (TPI), a literature-informed framework that summarizes the direction of CD4+T-cell lineage deviation using routinely measured serum markers. We integrate statistical associations and mechanistic evidence to relate five peripheral markers to CD4+ T-cell lineage states. Each marker was weighted by the number of pathways involved and the strength of its effect, forming a quantitative index that reflects an individual's CD4+T-cell lineage pattern.This framework is not only a way of modeling immune changes in AS but may also have potential value in immune stratification, risk assessment and the exploration of therapeutic strategies.peripheralserum markers and CD4+ T-cellT cell Perturbation Index