Unraveling the Intricacies of IBD: Insights into TIM1 and TIM3 Surface Proteins and their Intracellular Signaling Pathways in View of a Possible Treatment

Introduction The T cell immunoglobulin and mucin domain (TIM) receptors TIM1 and TIM3 are associated with T helper cells and act co-stimulatory or co-inhibitory respectively, leading to either T cell activation or apoptosis1-3. TIM proteins have been linked to the development of autoimmune disorders and inflammatory bowel disease (IBD)4-7. However, their specific role in IBD is still unexplained. Here, we investigate the possible connectivity between TIM receptors and the intracellular IL-2 inducible tyrosine kinase (ITK) in context with inflammation and colitis. ITK plays a crucial role as a regulator of T cell immune responses and is known as a driver of inflammation in ulcerative colitis8. We hypothesize that inhibition of TIM1 and stimulation of TIM3 prevents or improves the colitis outcome by influencing the ITK signaling pathway. The divergent effects of TIM1 and TIM3 on T cells make them a pivotal consideration in the context of ITK signaling and its association with IBD.

Material and methods Lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) from IBD patients and murine intestine samples were analyzed for the expression of TIM proteins. Furthermore, we tested the effects of stimulatory and inhibitory agents of TIM1 and TIM3 on intracellular ITK signaling. In vivo treatment with neutralizing antibodies against TIM receptors and mice with functional knockouts were used to decipher the role of TIM1 and TIM3 on induced colitis. Disease outcomes were evaluated through mini-endoscopy, in vivo imaging systems, and histological scoring. Overall, various methods such as FACS, ELISA, immunofluorescence staining, and qPCR were applied for a comprehensive analysis.

Results PBMCs from IBD patients showed no difference in TIM1 and TIM3 expression compared to healthy controls, whereas LPMCs from IBD patients showed elevated TIM protein levels on T cells in inflamed tissue compared to not inflamed areas. Similarly, a rise of TIM protein expression could be detected in inflamed tissue from mice and stimulated murine LPMCs. Blocking ITK counteracted this effect in isolated CD4+T cells. Furthermore, ITK activation could be downregulated by stimulating TIM3, whereas stimulating TIM1 enhanced ITK activity. Treatment with an antagonistic antibody against TIM1 showed beneficial effects in experimental colitis models. Moreover, knocking out TIM3 exacerbated colitis severity in vivo and led to increased pITK levels in vitro in LPMCs [1] [2] [3] [4] [5] [6] [7] [8].

Summary IBD patients, who have failed conventional therapies such as CsA or anti-TNF-Ab, require targeted therapeutic approaches that for example can inhibit the intracellular ITK signaling cascade. Here, we were able to show that TIM1 and TIM3 receptors in particular are promising targets for future specialized medication treating IBD. However, further research is required.

Hinweis

Dieser Artikel wurde gemäß des Erratums vom 10.06.2024 geändert.

Erratum

In the above mentioned article the order of the authors was not correct. Correct is: A. Knauss, M. Gabel, M. F. Neurath, B. Weigmann.

Im oben genannten Artikel war die Autorenreihenfolge nicht korrekt. Korrekt ist : A. Weich, L. Retzbach, M. Brand, T. Kudlich, A. Wannhoff , K. Caca, A. Meining.

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Publication History

Article published online:
13 May 2024