Unravelling nucleolar dysfunction in lymphocytes: from novel mechanism to diagnosis of (severe) combined immune deficiency

ongoing

LYNCID addresses critical gaps in our understanding of (severe) combined immune deficiencies ((S)CIDs), a group of debilitating inborn errors of immunity caused by T-cell dysfunction. Although over 100 (S)CID-causing genes are known, 30-40% of (S)CID patients remain molecularly undiagnosed, resulting in high mortality. Better knowledge and timely diagnosis of (S)CID represent critical unmet medical needs. Recently, my team has identified biallelic mutations in GTF3A, encoding transcription factor IIIA (TFIIIA), in (S)CID patients with early T-cell differentiation block. TFIIIA plays a critical housekeeping role by transcribing 5S ribosomal RNA, essential for ribosome assembly and nucleolar stress regulation. Intriguingly, patient-derived cells experience increased G2/M cell cycle arrest during chemically induced nucleolar stress, evidencing an impaired stress response. Based on this finding, I hypothesize that TFIIIA deficiency triggers (S)CID by impairing the nucleolar stress response, thus unveiling a completely novel disease mechanism still to be explored. Using TFIIIA-deficient patients as a model, alongside cellular and zebrafish models, LYNCID seeks to uncover the hidden interplay between nucleolar stress and (S)CID. We aim to 1) elucidate the role of TFIIIA in T-cell development and nucleolar stress response, 2) unravel nucleolar stress response in T-cell biology, and 3) develop the ‘Nucleolar Stress Index’, a diagnostic tool to detect altered nucleolar stress in molecularly undefined (S)CID patients. LYNCID spearheads (S)CID research by uncovering new (S)CID pathways and providing unprecedented insights into T-cell biology and nucleolar stress. We will develop cutting-edge diagnostics to improve patient care. Overall, by revealing the role of nucleolar stress, LYNCID will substantially advance our understanding of immune disorders and can open new therapeutic avenues in other nucleolar stress-related diseases including cancer and neurodegeneration.