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Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis
Masato Ogishi1,2, Rui Yang1, Rémy Rodriguez3,4
1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
The Journal of Experimental Medicine
|November 3, 2022
Summary
Inherited ITK deficiency causes severe tuberculosis (TB) by impairing the development and function of key interferon-gamma (IFN-γ) producing T cells. This study identifies a novel genetic cause of TB, highlighting ITK
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Inborn errors of interferon-gamma (IFN-γ) immunity are linked to tuberculosis (TB).
- Investigating genetic causes of severe TB is crucial for understanding immune deficiencies.
- Interleukin-2-inducible T-cell kinase (ITK) deficiency is typically associated with severe Epstein-Barr virus (EBV) disease, complicating immunological studies.
Purpose of the Study:
- To investigate the immunological consequences of inherited complete ITK deficiency in patients presenting with severe TB.
- To identify the specific T cell subsets affected by ITK deficiency and their impact on IFN-γ production.
- To establish a link between ITK deficiency and susceptibility to mycobacterial infections.
Main Methods:
- Clinical and immunological evaluation of three patients from two kindreds with severe TB and inherited ITK deficiency.
- Flow cytometry analysis of T lymphocyte populations (αβ, γδ, double-negative) and their phenotype (CD38, CD45RA, T-bet, EOMES).
- Assessment of IFN-γ production by patient T cells in response to various stimuli, including BCG vaccination, and comparison with a mouse model of ITK deficiency.
Main Results:
- Patients exhibited CD4+ αβ T lymphocytopenia with expanded populations of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes with a specific phenotype (CD38+CD45RA+T-bet+EOMES-).
- Itk-deficient mice models showed similar expansions of γδ T and DN αβ T lymphocytes.
- Patients' T cells demonstrated impaired IFN-γ secretion in response to mitogens, TCR stimulation, and BCG, indicating a broad defect in IFN-γ immunity.
Conclusions:
- Inherited complete ITK deficiency disrupts the development and function of multiple IFN-γ-producing T cell subsets.
- This immune defect provides a novel genetic explanation for severe tuberculosis in affected individuals.
- ITK plays a critical role in maintaining robust T cell-mediated immunity against mycobacterial infections.
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