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REGULATION OF T-CELL ACTIVATION DURING THE IMMUNE RESPONSE AGAINST INFECTIONS
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SYSNO ASEP 0580659 Druh ASEP A - Abstrakt Zařazení RIV O - Ostatní Název REGULATION OF T-CELL ACTIVATION DURING THE IMMUNE RESPONSE AGAINST INFECTIONS Tvůrce(i) Janušová, Šárka (UMG-J) ORCID
Štěpánek, Ondřej (UMG-J) RID, ORCIDCelkový počet autorů 2 Číslo článku L-30 Zdroj.dok. Czech Chemical Society Symposium Series
Roč. 21, č. 5 (2023)Poč.str. 1 s. Akce Annual meeting of the National Institute of Virology and Bacteriology (NIVB) /2./ Datum konání 02.10.2023 - 05.10.2023 Místo konání Kutná Hora Země CZ - Česká republika Typ akce EUR Jazyk dok. eng - angličtina Země vyd. CZ - Česká republika Klíč. slova T-CELL ACTIVATION ; INFECTION ; IMMUNE RESPONSE Obor OECD Immunology CEP LX22NPO5103 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UMG-J - RVO:68378050 Anotace T cells play a critical role in the immune system. Their activation and effector functions are tightly regulated. For the full activation, T cells require the antigenic signal as well as costimulatory signals through CD28 and TNF-receptor superfamily receptors, such as GITR, OX40, and CD137, which trigger downstream signaling events, including NF-κB or MAPK pathways to prolong T-cell survival, proliferation, and effector functions1.
Using mass spectrometry, we identified novel signaling components of the GITR and OX40 proximal signaling complexes, including A20-binding inhibitor of NF-κB1 (ABIN1), a polyubiquitin binding protein that serves as a negative regulator of TNFRI and MyD88 signaling. However, very little was known about its role in T cells2.
We addressed the role of ABIN1 in T cells using Abin1-/- mice. Antigenic stimulation of Abin1-/- CD8+ T cells showed more robust proliferation and increased expression of major effector molecules Granzyme B and IFNγ than WT control cells ex vivo. As Abin1-/- T cells showed higher phosphorylation of p38 kinase and the p38 inhibitor reduced the ex vivo proliferation and Granzyme B and IFNγ expression upon activation, we propose that Abin1-/- is a negative regulator of p38 activation.
The phenotypic analysis of the lymphocyte compartment of Abin1-/- mice showed increased regulatory T cell and decrease in CD8+ T cell populations. The analysis of WT + Abin1-/- mixed bone marrow chimeras showed that these effects are intrinsic. We crossed the Abin1-/- mice with OVA-specific OT I TCR transgenic Rag2-/- mice to prevent the overt inflammation observed in the mice and to study the intrinsic role of ABIN1 in CD8+ T cells, which were adoptively transferred to polyclonal congenic Ly5.1 mice. Abin1-/- OT-I T cells were hyperresponsive to cognate transgenic Listeria monocytogenes-OVA and LCMV-OVA infections and formed more short-lived effector cells than WT OT-I cells. They also showed higher infiltration of the cognate MC-38-OVA tumors than the control cells.
In conclusion, we uncovered that ABIN1 is a negative regulator of T-cell activation ex vivo and in vivo. As such, it is a potentially target for future immunomodulatory therapies.Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2024 Elektronická adresa http://ccsss.cz/index.php/ccsss/issue/view/41
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