A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Lymphocyte-specific protein tyrosine kinase (LCK) is crucial for T cell receptor (TCR) signaling.
• Genetic variants in LCK can lead to primary immunodeficiencies.

Purpose of the Study:

• To investigate the functional consequences of a novel LCK variant (P440S) in siblings with T cell lymphopenia.
• To elucidate the distinct pathogenic mechanisms of complete versus partial LCK loss-of-function using mouse models.

Main Methods:

• Clinical evaluation of siblings with the LCK P440S variant.
• In vitro assessment of T cell signaling and proliferation.
• Generation and analysis of Lck knockout and knock-in mouse models (Lck-/- and LckP440S/P440S).
• T cell depletion and regulatory T cell transfer experiments in mice.

Main Results:

• Siblings with homozygous LCK P440S variant presented with T cell lymphopenia, recurrent infections, and failure to thrive.
• LCK P440S variant T cells exhibited residual signaling and proliferation compared to complete LCK deficiency.
• Mouse models revealed that partial LCK loss (LckP440S/P440S) resulted in T cell lymphopenia and intestinal inflammation, unlike complete loss (Lck-/-).
• Intestinal inflammation in LckP440S/P440S mice was mediated by conventional T cells and prevented by regulatory T cell transfer.

Conclusions:

• The LCK P440S variant causes a distinct immunodeficiency characterized by impaired regulatory T cell function, leading to intestinal inflammation.
• Partial LCK loss-of-function has different clinical and immunological consequences compared to complete loss.
• Targeting T cell subsets may offer therapeutic strategies for LCK-associated disorders.