Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro

Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR...

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Main Authors: Kavita R. Manhas, Pamela A. Marshall, Carl E. Wagner, Peter W. Jurutka, Michelle V. Mancenido, Hannah Z. Debray, Joseph N. Blattman
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-01-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2022.746484/full
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author Kavita R. Manhas
Pamela A. Marshall
Carl E. Wagner
Peter W. Jurutka
Michelle V. Mancenido
Hannah Z. Debray
Joseph N. Blattman
author_facet Kavita R. Manhas
Pamela A. Marshall
Carl E. Wagner
Peter W. Jurutka
Michelle V. Mancenido
Hannah Z. Debray
Joseph N. Blattman
author_sort Kavita R. Manhas
collection DOAJ
description Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4β7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4β7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.
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spelling doaj.art-c0466005fefd484c87693411bca25afd2022-12-21T23:43:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-01-011310.3389/fimmu.2022.746484746484Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In VitroKavita R. Manhas0Pamela A. Marshall1Carl E. Wagner2Peter W. Jurutka3Michelle V. Mancenido4Hannah Z. Debray5Joseph N. Blattman6Biodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United StatesSchool of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United StatesSchool of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United StatesSchool of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United StatesSchool of Mathematical and Natural Sciences, Arizona State University West Campus, Glendale, AZ, United StatesBiodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United StatesBiodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University, Tempe, AZ, United StatesAltering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4β7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4β7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.https://www.frontiersin.org/articles/10.3389/fimmu.2022.746484/fullmigrationmucosalrexinoidsretinoic acidretinoidT-cell
spellingShingle Kavita R. Manhas
Pamela A. Marshall
Carl E. Wagner
Peter W. Jurutka
Michelle V. Mancenido
Hannah Z. Debray
Joseph N. Blattman
Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
Frontiers in Immunology
migration
mucosal
rexinoids
retinoic acid
retinoid
T-cell
title Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
title_full Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
title_fullStr Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
title_full_unstemmed Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
title_short Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro
title_sort rexinoids modulate effector t cell expression of mucosal homing markers ccr9 and α4β7 integrin and direct their migration in vitro
topic migration
mucosal
rexinoids
retinoic acid
retinoid
T-cell
url https://www.frontiersin.org/articles/10.3389/fimmu.2022.746484/full
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