Ruxolitinib-mediated Modulation and Dynamic Expression of P-glycoprotein in Human CD8+ T Cell Memory Subsets During Differentiation

A tétel rövid nézete
dc.contributor.advisorBacso, Zsolt
dc.contributor.authorBiwott, Kipchumba
dc.contributor.authorvariantKipchumba, Biwott
dc.contributor.departmentMolekuláris sejt- és immunbiológia doktori iskolahu
dc.contributor.submitterdepÁltalános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet
dc.date.accessioned2025-10-21T12:58:53Z
dc.date.available2025-10-21T12:58:53Z
dc.date.defended2025-11-06
dc.date.issued20251017
dc.description.abstractThe study investigated the interaction between ruxolitinib (RUX), an FDA-approved JAK1/2 inhibitor, and P-glycoprotein (Pgp/ABCB1/MDR1), an ATP-binding cassette transporter involved in drug resistance and immune regulation. Pgp exports xenobiotics and is expressed in immune cells, including T lymphocytes. While high Pgp expression is linked to poor responses in autoimmune diseases, it enhances the resilience of memory T cells, supporting immune recovery after chemotherapy. To evaluate this interaction, human primary T cells and NIH-3T3 MDR1 cells were used. RUX inhibited Pgp activity in a dose-dependent manner (at non-therapeutic levels), downregulated PD-1 and Pgp in activated T cells, activated basal Pgp ATPase activity, and interfered with verapamil-induced activation, suggesting functional modulation. Molecular analyses revealed that ABCB1 mRNA was high in unprimed T cells but declined with activation. RUX treatment upregulated ABCB1 in activated T cells, indicating its role as a transcriptional regulator. These findings may improve chemotherapy outcomes and aid in GVHD management. The effect of RUX on T-cell maturation showed a shift toward naive and central memory (Tcm) CD8+ T cells, with reduced effector and effector memory (Tem) subsets. This reprogramming may enhance therapeutic efficacy in myelofibrosis and immune disorders. Using an in vitro model, T cells were primed with JY antigen-presenting cells, and maturation was tracked over a month. RUX exposure promoted Pgp+ long-lived memory T cell maintenance and delayed effector differentiation. It also expanded CD127⁺ memory T cells, supporting long-term immune memory. In conclusion, this study demonstrates that RUX modulates Pgp function and T cell differentiation, with implications for autoimmune disease, transplantation, and cancer therapy. Targeting Pgp in memory T cells could improve the effectiveness of immunotherapies by enhancing memory cell survival and immune resilience.
dc.description.correctorSzerző kérésére javítottam az absztraktban egy elírást, illetve a rosszul felvett neveket. PF
dc.format.extent110
dc.identifier.urihttps://hdl.handle.net/2437/398068
dc.language.isoen
dc.subjectP-glycoprotein; Cytotoxic T lymphocytes; CTL memory subsets; Ruxolitinib; JY cells; T cell activation; JAK-STAT signaling immune modulation; TCR activation; UMAP; flow cytometer; Subsets.
dc.subject.disciplineElméleti orvostudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleRuxolitinib-mediated Modulation and Dynamic Expression of P-glycoprotein in Human CD8+ T Cell Memory Subsets During Differentiation
dc.title.translatedRuxolitinib által közvetített P-glikoprotein moduláció és dinamikus expresszió emberi CD8⁺ T-sejt memória alcsoportokban a differenciálódás során
dc.typePhD, doktori értekezéshu
Fájlok
Eredeti köteg (ORIGINAL bundle)
Megjelenítve 1 - 4 (Összesen 4)
Nincs kép
Név:
DISSERTATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (PHD)_Biwott_Kipchumba_20251017.pdf
Méret:
7.42 MB
Formátum:
Adobe Portable Document Format
Letöltés
Nincs kép
Név:
SHORT THESIS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (PHD)_Kipchumba Biwott_20251017.pdf
Méret:
925.83 KB
Formátum:
Adobe Portable Document Format
Letöltés
Nincs kép
Név:
INVITATION Kipchumba Biwott_20251017.pdf
Méret:
118.94 KB
Formátum:
Adobe Portable Document Format
Letöltés
Nincs kép
Név:
MEGHIVO Kipchumba Biwott_20251017.pdf
Méret:
123.12 KB
Formátum:
Adobe Portable Document Format
Letöltés
Engedélyek köteg
Megjelenítve 1 - 1 (Összesen 1)
Nincs kép
Név:
license.txt
Méret:
1.93 KB
Formátum:
Item-specific license agreed upon to submission
Leírás:
Letöltés
Gyűjtemények
Molekuláris Sejt- és Immunbiológia Doktori Iskola