Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization

• Published in: Haematologica (Roma) 2024-02, Vol.109 (2), p.444-457
• Main Authors: Ciudad, Marion, Ouandji, Sethi, Lamarthée, Baptiste, Cladière, Claudie, Ghesquière, Thibault, Nivet, Martin, Thébault, Marine, Boidot, Romain, Soudry-Faure, Agnès, Chevrier, Sandy, Richard, Corentin, Maillet, Thibault, Maurier, François, Greigert, Hélène, Genet, Coraline, Ramon, André, Trad, Malika, Predan, Valérie, Saas, Philippe, Samson, Maxime, Bonnotte, Bernard, Audia, Sylvain
• Format: Article
• Language: English
• Subjects: Aminopyridines; Anemia, Hemolytic, Autoimmune; Animals; Cell Therapy & Immunotherapy; Forkhead Transcription Factors - metabolism; Humans; Morpholines; Pyrimidines; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2023.282859

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195).