REGULATION OF T-CELL ACTIVATION DURING THE IMMUNE RESPONSE AGAINST INFECTIONS

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F23%3A00580659" target="_blank" >RIV/68378050:_____/23:00580659 - isvavai.cz</a>

Result on the web

<a href="http://ccsss.cz/index.php/ccsss/issue/view/41" target="_blank" >http://ccsss.cz/index.php/ccsss/issue/view/41</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

REGULATION OF T-CELL ACTIVATION DURING THE IMMUNE RESPONSE AGAINST INFECTIONS

Original language description

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.nUsing 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.nWe 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.nThe 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. nIn 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.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30102 - Immunology

Project

<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů