Background: The discrepancy between systemic and persistent arterial wall inflammation presents a significant challenge in the management of Takayasu’s arteritis (TAK) [1]. Previous research suggested that aberrant Th1 responses serves as a key mediator of sustained vascular inflammation in TAK [2].

Objectives: This study aims to investigate novel mechanisms within the vascular microenvironment that drive the persistent activation of Th1 responses.

Methods: The compositional features, functional profiles, and spatial characteristics of T-cell subsets in peripheral blood and arterial lesions of patients with TAK and control individuals（patients with giant cell arteritis, vascular Behçet’s disease, or non-inflammatory arterial malformations）were investigated by single-cell and spatial transcriptomic sequencing, multiplex immunofluorescence, and flow cytometry. In vitro experiments were conducted to explore the interactions between vascular smooth muscle cells (VSMCs) and key T-cell subsets, alongside the molecular mechanisms underpinning these interactions. A humanized mouse model of TAK was developed to confirm the role of these T-cell subsets in mediating vascular inflammation.

Results: CD4+ stem-like T cells (CD4+SL), characterized by CD4+TCF1 ^hi LEF1 ^hi ICOS ^hi , constitute a predominant subset of CD4+ T cells in both the peripheral blood mononuclear cells (PBMCs) and arterial tissue of patients with TAK. Within arterial tissue, these cells are primarily localized at stenotic lesions and are spatially adjacent to VSMCs. CD4+SL exhibit high expression of chemokine receptor CXCR4, facilitating their migration towards CXCL12, which is abundantly expressed in vascular lesions of TAK. In comparison to their counterparts in peripheral blood, CD4+SL acquire a Th1-like phenotype within the vascular microenvironment. Transcription factors (TFs) analysis indicates that IKZF1 and RUNX3 function as specific TFs for CD4+SL cells in peripheral blood and tissue, respectively. IL-33 is highly expressed in the arterial tissue of TAK patients, with VSMCs being the predominant cellular source. Inhibition of IL-33 signaling effectively prevents the acquisition of Th1 phenotype in CD4+SL induced by TAK tissue-conditioned medium. Furthermore, Th1-associated cytokines, including IFN-γ and TNF-α, synergistically enhance the expression and secretion of IL-33 in primary VSMCs derived from patients with TAK. Mechanistically, IKZF1 serves as a core TF in maintaining the stem-like properties of CD4+SL, while RUNX3 is critical in the IL-33-induced Th1-like phenotype without diminishing IKZF1 expression. Molecular docking studies indicate that RUNX3 and IKZF1 can bind to the same TF-binding motif within the T-bet promoter, suggesting their potential competitive regulation of T-bet transcription, which is crucial for determining the fate of CD4+SL. The pivotal role of CD4+SL in the vascular inflammation in TAK was demonstrated using a humanized mouse model reconstituted with either intact PBMCs (containing CD4+SL) or CD4+SL-depleted PBMCs.

Conclusions: Within the TAK vascular microenvironment, VSMCs and CD4+SL establish a feedforward loop mediated by IL-33 and Th1-related cytokines. This interaction may constitute a fundamental molecular basis for the persistence of vascular inflammation in patients with TAK.

REFERENCES: [1] Keser, G.; Aksu, K.; Direskeneli, H. Discrepancies between vascular and systemic inflammation in large vessel vasculitis: an important problem revisited. Rheumatology (Oxford) 2018, 57, 784-790, 10.1093/rheumatology/kex333. 17.

[2] Saadoun, D.; Garrido, M.; Comarmond, C.; Desbois, A.C.; Domont, F.; Savey, L.; Terrier, B.; Geri, G.; Rosenzwajg, M.; Klatzmann, D.; Fourret, P.; Cluzel, P.; Chiche, L.; Gaudric, J.; Koskas, F.; Cacoub, P. Th1 and Th17 cytokines drive inflammation in Takayasu arteritis. Arthritis Rheumatol 2015, 67, 1353-1360, 10.1002/art.39037.

Acknowledgments: NIL.

Disclosure of Interests: None declared.