Low CD4+ T-Cell Counts Track With Worse Tic Severity in Children

Tic disorders, including Tourette syndrome and chronic motor or vocal tic disorder, are among the most common childhood-onset neurodevelopmental conditions, yet the biological forces that determine how severe a child’s tics become remain poorly understood. A research team in Zhangjiagang, China, has now reported that a familiar player from the immune system, the CD4+ T cell, may carry a measurable signal about tic-related symptom burden. In a cross-sectional study of 41 newly diagnosed, treatment-naive children, the researchers found that lower absolute counts of circulating CD4+ T cells were associated with higher scores on the Yale Global Tic Severity Scale, the most widely used clinician-rated instrument for quantifying tic severity. The finding, published in Frontiers in Psychiatry, adds a peripheral immune dimension to a disorder usually framed in terms of brain circuits.

The study was conducted at Zhangjiagang Hospital affiliated to Soochow University between January 2022 and August 2025. The team enrolled children younger than 14 years who fulfilled DSM-5 diagnostic criteria for tic disorders at their first clinical visit and had never received tic-specific pharmacological treatment. This treatment-naive design matters: because tic-directed medications can themselves alter immune parameters, studying children before any intervention reduces a major source of confounding. Children with uncertain diagnoses, genetic or neurological disorders, clinically evident infections, chronic or malignant disease, known immunological or autoimmune disorders, or recent use of medications or vitamin supplements were excluded. The final sample comprised 29 boys and 12 girls with a mean age of 8.61 years.

Tic severity was assessed with the Yale Global Tic Severity Scale, or YGTSS, a clinician-rated instrument whose global severity score combines a total tic score, spanning motor and vocal tic domains with a possible range of 0 to 50, and an impairment score, also ranging from 0 to 50, for a possible total of 0 to 100. The mean global severity score in the cohort was 30.71, with the total tic and impairment components contributing nearly equally at 15.34 and 15.37, respectively. Because the global score merges tic manifestations and functional impairment, the primary finding should be read as an association with overall tic-related symptom burden rather than with tic frequency, intensity, or disability alone.

Alongside the severity assessment, the researchers drew on an unusually broad laboratory panel. Serum measurements covered 25-hydroxyvitamin D and its D2 and D3 fractions, plus the fat-soluble vitamins A, E, and K, each included for mechanistic reasons: vitamin D is an immunomodulatory secosteroid influencing antigen-presenting cells, cytokine production, and T-cell differentiation; vitamin A-derived retinoic acid regulates T-cell differentiation and immune tolerance; vitamin E acts as a membrane antioxidant modulating immune cell function; and vitamin K participates in sphingolipid metabolism in neural tissues. Immune variables included total lymphocyte count, T-, B-, and NK-cell percentages, CD4+ and CD8+ T-cell percentages and absolute counts, and the CD4/CD8 ratio. The mean serum 25(OH)D concentration was 20.90 ng/mL, and the mean CD4+ T-cell absolute count was 823.56 cells per microliter.

The statistical strategy was deliberately conservative for a small sample. Because the data were not normally distributed, the team used Spearman rank correlation, which captures monotonic associations without assuming linearity, and controlled for multiple testing across 15 laboratory variables using the Benjamini-Hochberg false discovery rate method. CD4+ T-cell absolute count showed the strongest inverse correlation with the YGTSS global severity score, with a Spearman rho of -0.474 and an unadjusted P value of 0.0017. Critically, this association survived FDR correction, with an adjusted P value of 0.0260. Total lymphocyte count, 25(OH)D3, and total 25(OH)D showed nominal inverse correlations but did not remain significant after correction. Vitamins A, E, and K showed essentially no association with severity at all.

The association then faced a tougher test: covariate-adjusted linear regression. Each laboratory variable was entered into a separate model adjusted for age, sex, and disease duration, with heteroscedasticity-consistent HC3 robust standard errors used to guard against non-normal residuals and influential observations in the small sample. The CD4+ T-cell association persisted after adjustment, with a coefficient of -0.018 and a 95 percent confidence interval of -0.031 to -0.005, and a P value of 0.0069. Expressed on a more interpretable scale, every 100 cells per microliter higher CD4+ count was associated with roughly 1.8 points lower on the YGTSS global severity score, assuming a linear relationship. No other laboratory variable reached nominal significance in the adjusted models. In a sensitivity analysis that additionally adjusted for total lymphocyte count, the inverse association persisted but the estimate was less precise and sat close to the nominal significance threshold.

The vitamin D results were more equivocal. When participants were grouped by serum 25(OH)D status using Endocrine Society criteria, 23 children fell below 20 ng/mL, 10 fell between 20 and 30 ng/mL, and 8 were at or above 30 ng/mL. The deficient group had the highest mean severity score at 34.43, and the overall omnibus difference among groups was significant, with a Kruskal-Wallis P value of 0.0073. But Dunn-Bonferroni pairwise testing identified only one significant contrast, between the deficient and 20-to-30-ng/mL groups, with an adjusted P value of 0.0077. The group at or above 30 ng/mL did not differ significantly from either other group, so the data showed no monotonic dose-response pattern. The authors characterized the vitamin D findings as exploratory and less robust than the CD4+ T-cell association, noting that the small and unequal group sizes may have produced unstable estimates.

What could a reduced CD4+ T-cell count mean biologically in a child with more severe tics? The authors offer several non-exclusive mechanisms. First, a lower circulating count may reflect immune redistribution or persistent immune activation, whereby activated T cells migrate from peripheral blood into inflammatory sites or lymphoid tissues. Second, it may indicate impaired immune regulation, particularly if regulatory T-cell function is reduced. Third, CD4+ alterations may interact with cytokine-mediated neuroinflammatory pathways that influence dopaminergic neurotransmission, microglial activation, and cortico-striato-thalamo-cortical circuit function, all of which are relevant to tic generation. Prior work supports this framing: a meta-analysis of pediatric Tourette syndrome reported reduced CD4+ T cells alongside increased proinflammatory cytokines such as IL-6 and TNF-alpha, and studies in children with tic disorders and allergic diseases have reported changes in CD3+ T cells, CD4+ T cells, and the CD4/CD8 ratio.

The authors are careful about what the finding does not establish. The study included no healthy control group, so the results concern severity-related associations within children with tic disorders and cannot determine whether immune or vitamin measures differ from healthy children. Lymphocyte subset values vary with age in children, and although analyses were adjusted for age, age-standardized z scores were unavailable, so the data do not show that CD4+ counts were abnormally low compared with age-matched peers. Body mass index, season of blood collection, sunlight exposure, dietary intake, allergic disease, and detailed psychiatric comorbidity data were also unavailable, and high-sensitivity C-reactive protein was available for only 24 of 41 participants, meaning subtle subclinical inflammation could not be fully excluded. Exploratory component analyses showed nominal inverse associations of CD4+ count with both the total tic score and the impairment score, but neither survived FDR correction, so the main association cannot be attributed specifically to tic manifestations or functional impairment.

The authors stress that the findings have no immediate role in diagnosing tic disorders, classifying patients, predicting clinical course, or selecting treatment, and do not support using vitamin D concentration or CD4+ T-cell count alone for any of these purposes. Current guidelines emphasize clinical assessment, functional impairment, comorbidities, and individualized management rather than biomarker-based classification. Evaluation of vitamin D status may still be appropriate when a child has established clinical risk factors for deficiency, independent of any proposed tic-related role. The observed CD4+ T-cell association should be regarded as a hypothesis-generating signal that requires validation in larger longitudinal and controlled studies with healthy controls, age-standardized immune measures, and detailed YGTSS item data. Until then, the idea that a routine blood count might whisper something about the severity of a child’s tics remains an intriguing lead rather than a clinical tool.

Subject of Research: Neuroscience

Article Title: Associations of vitamin status and T-lymphocyte subsets with tic severity in children: a cross-sectional study using the Yale Global Tic Severity Scale

Article References: Zhu, F., Gao, Y., Zhang, Z., Kang, S., Xu, W., & Zhang, J. (2026). Associations of vitamin status and T-lymphocyte subsets with tic severity in children: a cross-sectional study using the Yale Global Tic Severity Scale. Frontiers in Psychiatry, 17, Article 1903047. https://doi.org/10.3389/fpsyt.2026.1903047

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1903047

Keywords: tic disorders, Tourette syndrome, CD4+ T cells, vitamin D, YGTSS, pediatric neuroimmunology, Associations, vitamin, status, T-lymphocyte, subsets, severity