Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling
| Autor: | Suresh K. Mendu, Marta E. Stremska, Bimal N. Desai, Julia K. Krupa, Clare A. Parker, Michael S. Schappe, Eric J. Stipes, Jason S. Rogers, Justin S. A. Perry, Emily K. Moser, Thomas J. Braciale |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
TRPM Cation Channels Mice Transgenic chemical and pharmacologic phenomena Thymus Gland T-Lymphocytes Regulatory Biochemistry Article Immune tolerance Mice 03 medical and health sciences 0302 clinical medicine TRPM7 hemic and lymphatic diseases medicine Animals Molecular Biology Transcription factor STAT5 030304 developmental biology 0303 health sciences biology Cell growth Effector Chemistry FOXP3 hemic and immune systems Cell Biology Cell biology Cytokine biology.protein Interleukin-2 Female Gene Deletion 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Sci Signal |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.abb0619 |
| Popis: | The thymic development of regulatory T (T(reg)) cells, crucial suppressors of the responses of effector T (T(eff)) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of T(reg) cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of T(reg) cells in mice and led to a substantially higher frequency of functional T(reg) cells in the periphery. In addition, TRPM7-deficient mice were resistant to T cell–driven hepatitis. Deletion of Trpm7 and inhibition of TRPM7 channel activity by the FDA-approved drug FTY720 increased the sensitivity of T cells to the cytokine interleukin-2 (IL-2) through a positive feed-forward loop involving increased expression of the IL-2 receptor α-subunit and activation of the transcriptional regulator STAT5. Enhanced IL-2 signaling increased the expression of Foxp3 in thymocytes and promoted thymic T(reg) (tT(reg)) cell development. Thus, these data indicate that inhibiting TRPM7 activity increases T(reg) cell numbers, suggesting that it may be a therapeutic target to promote immune tolerance. |
| Databáze: | OpenAIRE |
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