POS0062 ICOS+ T HELPER 2 CELLS PROMOTE THE PROGRESSION OF SYSTEMIC SCLEROSIS RELATED INTERSTITIAL LUNG DISEASE
Authors: H. Zhu, Y. Wu, Y. Zhang, H. Chen, D. Wang
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Among all complications of systemic sclerosis, interstitial lung disease (ILD) is the most common complication with poor prognosis and limited clinical treatment options. In SSc, T helper 2 cells perform as important pathogenic factors, and inducible co-stimulator (ICOS) participate in Th2 differentiation and selective IL-4 expression. However, the identity of the relevant ICOS<sup>+</sup> Th2 cells and their contribution to inflammation and fibrosis in SSc are still unknown. <h3>Objectives:</h3> This study aims to investigate the function and clinical significance of a new subgroup of Th2 cells in SSc. <h3>Methods:</h3> The leukocyte landscape of PBMCs from SSc patients and healthy controls was mapped using mass cytometry (cytometry by time-of-flight detection [CyTOF]). Flow cytometry analyses of human PBMCs were conducted to examine CD4<sup>+</sup>CXCR5<sup>-</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> cells. Human lung fibroblasts were cocultured with differentiated CD4<sup>+</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> cells and then were tested for their mRNA expression of fibrotic factors. SSc-ILD model was conducted by tracheal instillation of bleomycin. And the frequency of CD4<sup>+</sup>CXCR5<sup>-</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> cells were tested in lung, spleen and peripheral blood. Rag-deficient mice was injected with in vitro differentiated CD4<sup>+</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> cells and pulmonary inflammation and fibrosis were evaluated by Masson and HE staining. <h3>Results:</h3> A group of CD4<sup>+</sup>CCR4<sup>+</sup>ICOS<sup>+</sup> T cells were screened through CyTOF and significantly increased in SSc-ILD patients. This subset was defined as ICOS+Th2 cells, as they didn't express biomarkers of Tfh cells (CXCR5), Th1 cells (CXCR3), and Th17 cells (CCR6). And besides, CCR4 is preferentially expressed on Th2 cells. A significantly higher frequency of CD4<sup>+</sup>CXCR5<sup>-</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> T cells, most of which (~90%) were CCR4<sup>+</sup> T cells, in peripheral blood of SSc-ILD patients could also be detected by flow cytometry. Futhermore, the upregulated frequency of CD4<sup>+</sup>CXCR5<sup>-</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> T cell were also found in the lung and spleen of BLM-induced pulmonary fibrosis mice model. In vitro, human lung fibroblasts could be differentiated to α-SMA<sup>+</sup>myofibroblasts and product more collagen after being cocultured with differentiated CD4<sup>+</sup>ICOS<sup>+</sup>IL-4<sup>+</sup> T cells (ICOS<sup>+</sup> Th2 cells). In vivo, differentiated ICOS<sup>+</sup> Th2 cells, which were injected into Rag-deficient mice, could induce pulmonary inflammation and fibrosis. <h3>Conclusion:</h3> Our results together demonstrated the positive expression for the ICOS on Th2 cells, and provide functional evidence that ICOS<sup>+</sup> Th2 cells could mediating to SSc-ILD by secreting IL-4. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>