# The role of SERPINB1 in T cell function and its contribution to human diseases

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $646,268

## Abstract

PROJECT SUMMARY
 Primary immunodeficiencies (PIDs) are a group of monogenic diseases caused by inborn errors of immunity
(IEI) that confer risk of severe infection, autoimmunity, and cancer. The genetic and immunological study of IEI
is instrumental to understand mechanisms of human immunity and to manage and treat patients with PIDs. Their
study is also important to understand more common diseases associated with genetic variants in the same
genes. However, despite the relevance and importance of studying PIDs from the basic science and clinical
points of view, half of the PID patients lack a genetic diagnosis. By studying a patient with a PID of unknown
genetic etiology that confers susceptibility to severe mycobacterial disease, we identified a nonsense mutation
in SERPINB1. Using a combination of population genetics, biochemistry, and molecular biology, we showed that
this is the first case of SERPINB1 complete deficiency ever described. SERPINB1 is an intracellular serine
protease suicide inhibitor. Its absence in mice causes uncontrolled intracellular protease activity, leading to
neutrophil death and subsequent neutropenia. Interestingly, our patient does not display any neutrophil
abnormality, but instead, our in-depth immunological characterization showed a reduction in the frequency of
activated T cells and CD4+ memory T cells. Our findings suggest that SERPINB1 has a previously unknown
function in T cells and antimycobacterial immunity. Our data also indicates that SERPINB1 orchestrates an
intracellular protease-mediated pathway essential for T cell activation and survival. Given our findings, this
application will test the hypothesis that SERPINB1 is critical for human T cell activation and, by controlling
intracellular protease activity, to human diseases. Capitalizing on the unique opportunity that this patient offers
to understand the function of human SERPINB1, we propose three complementary approaches. In Aim 1, we
will characterize the immunological consequences of SERPINB1 deficiency on T cell activation and CD4+ T cell
differentiation. We will also study the transcriptional consequences of SERPINB1 deficiency in T cells. With this,
we will uncover a previously unknown function of SERPINB1 in human T cells. In Aim 2, we will identify and
characterize the pathways orchestrated by SERPINB1 in T cells. The absence of SERPINB1 unleashes the
action of intracellular proteases. This rare mechanism of PID will allow for chemical inhibition of these proteases
for therapeutic purposes. Furthermore, characterizing the SERPINB1-dependent antimycobacterial mechanisms
will lead to the identification of additional IEI in its pathway in patients lacking a genetic diagnosis. In Aim 3, we
will perform phenome-wide association studies (pheWAS) to identify associations between genetic variants in
the SERPINB1 pathway and additional human diseases. This reverse genetic approach will expand what we will
learn from the study of a rare disease to bene...

## Key facts

- **NIH application ID:** 10881953
- **Project number:** 5R01AI168210-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ruben Martinez Barricarte
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $646,268
- **Award type:** 5
- **Project period:** 2023-07-05 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881953

## Citation

> US National Institutes of Health, RePORTER application 10881953, The role of SERPINB1 in T cell function and its contribution to human diseases (5R01AI168210-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10881953. Licensed CC0.

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