T Cell Subsets Are Altered Off Season in Patients With Allergic Rhinitis

Allergic rhinitis (AR) is a common chronic inflammatory condition of the upper airways caused by an inappropriate immune response to environmental allergens [1]. While classically attributed to Th2-mediated responses, emerging evidence points to a broader immunological involvement, including dysregulation among memory T-helper (Th), T follicular helper (Tfh), and regulatory T (Treg) cells. The persistence of symptoms in many patients even outside the pollen season highlights a gap in our understanding of the underlying immunopathology [1, 2]. In this study, we aimed to investigate systemic T cell dysregulation in AR patients during the pollen-free period, focusing on memory Th subsets, Tfh polarization, and Treg phenotypes. We recruited 23 AR patients and 32 healthy controls and collected peripheral blood mononuclear cells (PBMCs) for analysis. Using multiparameter flow cytometry, we examined the distribution and phenotype of CD4+ memory T cells based on CD49d and CD27 expression, and characterized the major Th subsets (Th1, Th2, Th17, Th1/Th17) as well as Tfh and Treg populations. An overview of the study design, the T cell-mediated immune response in AR, and key findings are presented in Figure 1. Detailed methods are provided in the Supporting Information. Our results revealed that memory Th1/Th17 cell subsets were significantly decreased in AR patients, particularly CD49−CD27+ and CD49d−CD27− phenotypes (Figure 2; top left). This may reflect a shift away from Th1/Th17-driven responses and toward a more Th2-skewed systemic profile [3]. Notably, we found an expansion of Tfh2 and Tfh17 cells in AR patients, with a corresponding reduction in Tfh1 and Tfh1/Tfh17 cells (Figure 2; top right). Tfh2 cells are known to enhance B cell differentiation and class switching to IgE, implicating them in allergy persistence and exacerbation [4, 5]. Treg populations were also altered, with significantly lower frequencies of CD49+CD27− and CD49d−CD27− Tregs, suggesting a diminished regulatory capacity within the T cell compartment (Figure 2; bottom left) [2, 6]. Together, these findings point to a state of immune imbalance in AR patients that persists even outside allergen exposure periods. The combined expansion of Tfh2 and Tfh17 subsets with the reduction of key regulatory T cell populations may create a conducive environment for rapid immune activation upon seasonal re-exposure to allergens. This highlights the need to consider baseline immune dysregulation when developing long-term therapeutic strategies for AR. Conclusion: Our study demonstrates that AR is characterized by persistent systemic alterations in memory Th, Tfh, and Treg cell compartments during the pollen-free season. These findings challenge the assumption that immune homeostasis is restored outside allergen exposure and suggest that targeting T cell polarization may improve management of allergic diseases. Conceptualization: M.J., E.H., S.K.G., L.-O.C. Data Curation: M.J., E.H. Formal analysis: M.J., E.H. Investigation: M.J., E.H. Methodology: M.J., E.H., S.K.G., L.-O.C. Project administration: M.J., E.H., S.K.G., L.-O.C. Resources: M.J., E.H., E.P., M.P., A.K. Supervision: E.H., S.K.G., L.-O.C. Validation: M.J., E.H. Writing – original draft: M.J. Writing – review and editing: M.J., E.H., E.P., M.P., A.K., S.K.G., O.W., L.-O.C. All authors have confirmed the manuscript. We thank all participants for their contributions to this study. The authors declare no conflicts of interest. The data sets used and/or analyzed in this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.