Work

Murine T lymphocytes bearing an activating mutation in Itk show enhanced response to infection 3276

Year: 2025

Type: article

Abstract: Description IL-2 Inducible T cell Kinase (ITK) is an important regulator of TCR-mediated immune responses. Though not essential for TCR signaling, ITK activity generates graded expression of TCR-induced genes, highlighting ITK’s role in fine-tuning T cell signaling, especially under conditions of low TCR affinity or low antigen abundance. To date, nothing is known about the consequences of increasing, rather than decreasing, ITK activity in T cells. Using insights gained from biochemical studies of BTK in B cells, we generated a knock-in mouse model (ITK-E616K) carrying a mutation predicted to destabilize the autoinhibited form of ITK. Initial phenotyping of ITK-E616K naïve CD8 T cells showed no developmental differences from wild-type T cells indicating unaffected T-cell development. In vitro stimulation with anti-CD3/CD28 showed increased IRF4 upregulation in ITK-E616K T cells, a transcription factor shown to be tightly regulated by ITK. In an LCMV infection model, ITK-E616K knock-in mice exhibited a higher frequency of virus-specific CD8 T cells at 7 days post-infection (dpi). Similarly, preliminary co-transfer studies using an Ova-expressing Listeria monocytogenes infection model also showed E616K OT-I T cells outnumbering wild-type counterparts by over 2-fold at 7 and 14 dpi with enhanced Granzyme B and IFN-γ production potentially indicating increased cytolytic activity. These findings will help further elucidate ITK’s role in tuning TCR signaling and modulating T-cell activation. Funding Sources Supported by NIH/NIAID (RO1 AI043957). The Barbara Davis Center Cell and Tissue Analysis Core at the University of Colorado Diabetes Research Center (funded by NIH/NIDDK P30-DK116073) was utilized for flow cytometry experiments. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1094

Authors: Alayna M. Rosales, Mary Jessamine Michaels-Foster, Jennifer L. Matsuda, Amy H. Andreotti, Leslie J. Berg

Institutions: University of Colorado Anschutz, Iowa State University

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases