Sex-Based Immunological Differences in Multisystem Inflammatory Syndrome in Children: Potential Role of T R3-56 cells for Pathogenesis, Diagnosis, and Therapy

Flavia Carriero¹Monica Gelzo^2,3Valentina Rubino²Giulia Scalia³Alice Castaldo^2,4Vincenzo Tipo⁴Antonietta Giannattasio⁴Carolina D'anna⁴Giuseppina Ruggiero²Giuseppe Castaldo^2,3*Giuseppe Terrazzano^1*

• ¹University of Basilicata, Potenza, Italy
• ²University of Naples Federico II, Naples, Campania, Italy
• ³CEINGE Advanced Biotechnologies, University of Naples Federico II, Naples, Campania, Italy
• ⁴Santobono Children's Hospital, Naples, Campania, Italy

Multisystem Inflammatory Syndrome in Children (MIS-C) is characterized by immune dysregulation, exhibiting clinical and immunological features reminiscent of autoimmune processes, although its underlying mechanisms remain incompletely understood. This study examines immune system alterations in MIS-C patients, focusing on TR3-56 lymphocytes, a novel population of regulatory T cells. Our findings reveal a positive correlation between circulating TR3-56 cells and regulatory T cells, suggesting a potential immunoregulatory role in MIS-C pathogenesis. Furthermore, we identified significant sex-based differences in immune responses. Male patients exhibit higher percentages of TR3-56 lymphocytes and increased expression of T cell activation markers, which correlate with greater disease severity. Conversely, female patients display immune profiles characterized by stronger immune T cell memory and regulatory responses, potentially helping to modulate inflammation. These findings highlight the relevance of considering sex-based differences in immune responses to MIS-C and suggest that TR3-56 lymphocytes may serve as novel biomarkers and potentially as therapeutic targets. Our study enhances the understanding of immune dysregulation in MIS-C and underscores the need for sex-specific therapeutic strategies to improve patient outcomes.