Authors:	Schwarz, Josephin
Title:	Role of IL-10 and beta-catenin signaling in dendritic cells during acute and latent mCMV infection
Online publication date:	12-Dec-2022
Year of first publication:	2022
Language:	english
Abstract:	Dendritic cells (DC) are the most important antigen-presenting cells of the immune system and play a central role in the initiation of an anti viral immune response by driving effector T cell (Teff) activation and regulatory T cell (Treg) induction. IL-10 is an essential regulatory cytokine during mutual interaction between Teff, Treg and DC during immunity to infection. During latent mCMV infection IL-10 limited the CD8+ T cell expansion but to what extent DC are targets or relevant sources of IL-10 during mCMV infection remains elusive. Another pathway associated with a tolerogenic DC function is the beta-catenin signaling pathway. The stabilization of β-catenin in DC mediated a pro-inflammatory function and promoted the development of CD8+ T cell responses in the context of a viral infection but whether and to what extent β-catenin signaling in DC affects the immunity and persistence of mCMV is not known. To investigate the role of IL-10 production by DC and IL-10 as well as beta-catenin signaling in DC during acute and latent mCMV infection, we used transgenic mice with a CD11c-specific deficiency of IL-10, IL-10R and beta-catenin or expression of a stabilized form of beta-catenin in CD11c+ cells (referred to as IL 10-CD11cdel, IL 10R-CD11cdel, beta-cat-CD11cdel and beta-cat-CD11c/EX3 mice). First, we established an intranasal (i.n.) mCMV infection model more closely reflecting the natural route of infection. For this purpose, we determined the CD8+ T cell response by MHC I specific Tetramer staining and observed a maximum frequency of M38 Tetramer binding mCMV-specific CD8+ T cells at 14 days post infection (p.i.), while the M45 Tetramer response was much weaker and peaked at 7 days p.i.. Based on these findings, we examined the role of DC in beta-catenin and IL-10 signaling during acute mCMV infection 14 days p.i. using the M38 Tetramer. After acute mCMV infection, no significant differences in the magnitude of the mCMV-specific CD8+ T cell responses and Treg differentiation were detected in IL 10-CD11cdel and IL 10R-CD11cdel mice. Moreover, latently infected IL 10R-CD11cdel mice showed neither an influence nor a memory inflation (MI) of mCMV-specific CD8+ T cells. These results indicate that DC IL-10 production and signaling does not play an essential role in the regulation of anti viral CD8+ T cell responses during acute and/or latent mCMV infection. Furthermore, the deletion of beta-catenin in CD11c+ cells did not affect the mCMV-specific CD8+ T cell response and Treg differentiation, while the stabilization of β-catenin in CD11c+ cells resulted in a significant expansion of FoxP3+ CD4 Treg in the steady state as well as during acute mCMV infection. This expansion of Treg numbers was due to higher numbers of thymus derived FoxP3+ CD4 Treg. In beta-catCD11c/EX3, splenic DC exhibited a shift toward increased XCR 1+ cDC1 and diminished CD172alpha+ cDC2. The mCMV specific CD8+ T cell response showed similar expansion in beta-catCD11c/EX3 and control mice, whereas the mCMV specific CD8+ T cell subpopulations revealed a modification in the distribution of pulmonary effector memory CD8+ T cells. Therefore, we investigated the impact of β-catenin signaling in latently infected beta-catCD11c/EX3 mice. The mCMV specific CD8+ T cell response was comparable in beta-catCD11c/EX3 compared to control mice and revealed no MI, while the further fractionation into subpopulations displayed a shift toward increased conventional effector memory T cells (cTEM) and reduced double positive effector T cells (DPEC) in lung and spleen of beta-catCD11c/EX3 mice, associated by increased FoxP3+ CD4 Treg. These data suggest an important role of β-catenin in DC for the induction of FoxP3+ CD4 Treg and possibly CD8+ memory T cells during mCMV infection.
DDC:	500 Naturwissenschaften 500 Natural sciences and mathematics
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie Sonderforschungsbereiche (SFB)
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8456
URN:	urn:nbn:de:hebis:77-openscience-bd6c08dc-e10b-49e6-a8f6-62fbe1a0babe4
Version:	Original work
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	http://rightsstatements.org/vocab/InC/1.0/
Extent:	ix, 166 Blatt ; Diagramme
Appears in collections:	JGU-Publikationen