Collaboration in action: New study identifies SIT1 as a key regulator of human immune responses

The study, co-led by NCMBM Director Janna Saarela, highlights the strength of collaboration across the Nordic EMBL Partnership and beyond, bringing together expertise in human genetics, immunology, advanced imaging, and multi-omics from research groups across Finland, Norway, Germany, and Austria.

The work was undertaken by co-first authors Pu Chen, a PhD student at FIMM and visiting researcher at NCMBM, and Kim My Le, researcher at the University of Helsinki and at Helsinki University Hospital.

Understanding the immune system’s “brakes”

T cells are an essential part of the immune system, helping the body fight against pathogens and detect abnormal cells, including cancer cells. Their activity must be tightly regulated: too little activation can leave the body vulnerable to infections, while too much can lead to inflammation or autoimmune disease.

The researchers focused on a protein called SIT1, which acts as a molecular “brake” on T cell activation. While earlier studies in mice had suggested that SIT1 helps fine-tune immune responses, very little was known about its role in humans.

In the new study, the team identified the first known human case of complete SIT1 deficiency. The researchers discovered a rare homozygous splice-site variant in the SIT1 gene that resulted in a total loss of the SIT1 protein and its function. The variant appears to be enriched in the Finnish population. To confirm the genetic link identified in one patient, the team used CRISPR-Cas9 gene editing to disrupt SIT1 in healthy T cells and RNA transfection to introduce intact SIT1 in patient-derived cells. These experiments provided strong evidence that SIT deficiency alters T cell function and drives the disease.

The patient investigated in the study was a 48-year-old man with a history of recurrent Hodgkin’s lymphoma, susceptibility to Human papillomavirus, and combined immunodeficiency. By combining multi-omics analyses with advanced super-resolution imaging, the team was able to characterize how the loss of SIT1 affected immune cell function.

Overactive T cells and impaired immune defence

The researchers found that the absence of SIT1 caused T cells to become overactivated and hyperproliferative. At the same time, important immune functions were impaired, including the ability of CD8⁺ T cells to destroy abnormal or infected cells effectively.

The study also revealed that SIT1 is involved in the organisation of the “immune synapse”, the specialised contact point through which T cells transfer their cytotoxic granules to target cells. Interestingly, the protein was found not only at the cell membrane, but also in intracellular vesicles, suggesting a broader role in coordinating immune signalling and vesicle trafficking.

These findings help explain how deficiency of SIT1 may contribute to immune dysregulation, increased susceptibility to infections, and a higher risk of lymphoid malignancies such as Hodgkin’s lymphoma.

Co-first author Pu Chen, in the Saarela group, says:

“This study gives us new insight into how the immune system stays balanced. By identifying the role of SIT1 in human immunity, we hope these findings can help improve the diagnosis and understanding of patients with rare immune disorders and related cancers.”

Implications for diagnosis and future therapies

The discovery expands current understanding of inborn errors of immunity, a group of rare genetic disorders that affect the immune system. According to Janna Saarela, co-senior author of the study:

“Identifying SIT1 as a central regulator of T cell activation provides important new knowledge of T cell regulation and can improve the diagnosis of patients with immunodysregulatory diseases.”

The study also illustrates how the Nordic EMBL Partnership enables researchers to address complex biomedical questions through interdisciplinary collaboration across institutions and countries, creating opportunities to translate fundamental discoveries into improved understanding of human disease.

The work also opens new avenues for future research into immune regulation and potential therapeutic strategies targeting T cell signalling pathways.

Although the findings are based on a single patient and laboratory models, the study establishes SIT1 as an important component of human immune homeostasis and highlights the need for further investigations in additional patients and disease settings.

Original publication

Homozygous loss-of-function mutation in SIT1 leads to combined immunodeficiency due to dysregulated T cell receptor signaling. Pu Chen, Kim My Le, Weiwei Li, Francisca Hinrichsen, Xiaonan Liu, Ragnhild Selvig Braathen, Nanni Mamia, Monika Szymanska, Zhuokun Li, Luca Trotta, Henrikki Almusa, Katariina Mamia, Virpi Glumoff, Peter Holland, Simon Anders, Artem Kalinichenko, Meri Kaustio, Mikko R.J. Seppänen, Emma Maria Haapaniemi, Markku Varjosalo, Timi Martelius, Juha Grönholm, Janna Saarela

You can read the full publication from The Journal of Allergy and Clinical Immunology, DOI: 10.1016/j.jaci.2026.03.030