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Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells./
作者:	Alvarez, Fernando.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	282 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
Contained By:	Dissertations Abstracts International82-10B.
標題:	Cancer. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383727
ISBN:	9798708719560

Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells.
Alvarez, Fernando.

Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 282 p.

Source: Dissertations Abstracts International, Volume: 82-10, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Regulatory T cells (TREG) are a specialized subset of CD4+ T cells that express the forkhead-box p3 (Foxp3) transcription factor, the master-regulator driving their suppressive phenotype. These cells can acquire tissue-specific adaptations that enable them to migrate and accumulate at mucosal surfaces where they play a critical, non-redundant, role in the maintenance of immune homeostasis. However, it remains to be understood how TREG cells modulate their suppressive function during an infection, when an effective immune response is required. Using an unbiased screen to study the transcriptional changes that dictate the fate of TREG cells in inflammation, we identified the differential expression of IL-1 alarmin receptors between TREG cells that maintained or TREG cells that lost Foxp3 expression. Alarmins are small molecules released upon cellular damage by structural and immune cells to communicate the level of danger to the surrounding milieu. Thus, we hypothesized that IL-1 alarmins dictate the functional adaptation of TREG cells at mucosal surfaces.In this work, we describe how IL-1β, IL-33 and IL-18, play critical roles in the local adaptation of TREG cells to mucosal inflammation. First, we demonstrate using both TH1 or TH17-dominant viral and fungal infections that IL-33 and IL-1β signaling dictate the balance between suppressive (IL-33R/ST2+) or permissive (IL-1R1+) TREG populations that orchestrates the immune response. Second, using a viral infection characterized by an exacerbated TH2 response, we demonstrate that the pro-suppressive effect of IL-33 on ST2+ TREG cells is context dependent, as it is dampened by STAT6 signaling. Third, we uncovered that in the course of viral and parasitic infection a population of TREG cells gain the ability to respond to IL-18 which, in turn, drives the proliferation and the expression of IFNy in these cells and impairs their suppressive ability. Collectively, these results reveal that IL-1β, IL-33 and IL-18 provide a dynamic signal to distinct populations of mucosa-adapted TREG cells that orchestrates the establishment of an effective and controlled adaptive response. Understanding how TREG cells modulate their adaptation to local tissue environments is key towards developing targeted therapies in autoimmune, infectious and oncologic diseases.

ISBN: 9798708719560Subjects--Topical Terms:

634186
Cancer.
Subjects--Index Terms:

IL-1 family of alarmins

Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells.
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245 1 0 $a Functional Characterization of the Role of the IL-1 Family of Alarmins in the Mucosal Adaptation of Regulatory T Cells.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 282 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
500 $a Advisor: Fritz, Jorg;Piccirillo, Ciriaco.
502 $a Thesis (Ph.D.)--McGill University (Canada), 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Regulatory T cells (TREG) are a specialized subset of CD4+ T cells that express the forkhead-box p3 (Foxp3) transcription factor, the master-regulator driving their suppressive phenotype. These cells can acquire tissue-specific adaptations that enable them to migrate and accumulate at mucosal surfaces where they play a critical, non-redundant, role in the maintenance of immune homeostasis. However, it remains to be understood how TREG cells modulate their suppressive function during an infection, when an effective immune response is required. Using an unbiased screen to study the transcriptional changes that dictate the fate of TREG cells in inflammation, we identified the differential expression of IL-1 alarmin receptors between TREG cells that maintained or TREG cells that lost Foxp3 expression. Alarmins are small molecules released upon cellular damage by structural and immune cells to communicate the level of danger to the surrounding milieu. Thus, we hypothesized that IL-1 alarmins dictate the functional adaptation of TREG cells at mucosal surfaces.In this work, we describe how IL-1β, IL-33 and IL-18, play critical roles in the local adaptation of TREG cells to mucosal inflammation. First, we demonstrate using both TH1 or TH17-dominant viral and fungal infections that IL-33 and IL-1β signaling dictate the balance between suppressive (IL-33R/ST2+) or permissive (IL-1R1+) TREG populations that orchestrates the immune response. Second, using a viral infection characterized by an exacerbated TH2 response, we demonstrate that the pro-suppressive effect of IL-33 on ST2+ TREG cells is context dependent, as it is dampened by STAT6 signaling. Third, we uncovered that in the course of viral and parasitic infection a population of TREG cells gain the ability to respond to IL-18 which, in turn, drives the proliferation and the expression of IFNy in these cells and impairs their suppressive ability. Collectively, these results reveal that IL-1β, IL-33 and IL-18 provide a dynamic signal to distinct populations of mucosa-adapted TREG cells that orchestrates the establishment of an effective and controlled adaptive response. Understanding how TREG cells modulate their adaptation to local tissue environments is key towards developing targeted therapies in autoimmune, infectious and oncologic diseases.
520 $a Les lymphocytes T regulateurs (TREG) sont une population de lymphocytes T CD4+ qui expriment forkhead-box P3 (Foxp3), un facteur de transcription qui joue un role cle dans l'expression des fonctions suppressives de la cellule. Ces cellules s'adaptent aux conditions inflammatoires pour pouvoir migrer et survivre en grand nombre dans les muqueuses ou elles jouent un role critique dans le maintien de l'homeostase immunitaire. Toutefois, nous ne savons pas encore comment les TREG modifient leur fonction suppressive lors d'une infection ou une reponse immunitaire efficace est requise. En analysant des changements dans le programme transcriptionnel de TREG lors d'inflammation, nous avons identifies que des recepteurs d'alarmines de la famille de l'IL-1 etaient preferentiellement exprimes entre des TREG qui ont maintenu et ceux qui perdu l'expression de Foxp3. Les alarmines, de petites molecules activees lors de dommage cellulaire, sont un moyen par lequel les cellules epitheliales et immunitaires communiquent le niveau de danger. Nous avons donc emis l'hypothese que ces alarmines modulent differemment la fonction et le sort des cellules TREG au fil de la reponse immunitaire.A travers cette these, nous demontrons que l'IL-1β, l'IL-33 et l'IL-18, jouent un role critique dans l'adaptation des TREG. En premier lieu, nous demontrons que l'IL-33 et l'IL-1β dictent la balance locale de TREG suppressifs (IL-33R/ST2+) ou permissifs (IL-1R1+) qui sont essentiels a la reponse antivirale et antifungique orchestree par des lymphocytes TH1 et TH17. En second lieu, nous demontrons que la fonction suppressive des TREG ST2+ depend du contexte inflammatoire puisque lors d'une infection virale caracterisee par une reponse TH2 elle est attenuee par un signal STAT6. Troisiemement, dans le cadre d'une infection virale et parasitaire, une population de cellules TREG acquiert la capacite de repondre a l'IL-18, ce qui les menent a produire de l'IFNy et bloque leur capacite suppressive. Collectivement, ces resultats demontrent que l'IL-1β, l'IL-33 et l'IL-18 offrent un signal qui dicte l'adaptation des cellules TREG a la muqueuse de maniere a faciliter une reponse immunitaire efficace et controlee. Une connaissance des signaux qui dictent l'adaptation des cellules TREG au site d'inflammation ouvre la voie au developpement de therapies ciblees dans le cadre de maladies auto-immunes, infectieuses et oncologiques.
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653 $a IL-1 family of alarmins
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