Interleukin-12-Producing CD103⁺CD11b⁻CD8⁺Dendritic Cells Are Responsible for Eliciting Gut Intraepithelial Lymphocyte Response against Encephalitozoon cuniculi

Abstract

Microsporidia, which belong to the kingdom Fungi, are important opportunistic pathogens in HIV-infected populations and organ transplant recipients that are often associated with a broad range of symptoms, such as diarrhea, nephritis, and encephalitis. Natural infection occurs via the oral route, and as a consequence, gut immunity plays an important role in restricting the dissemination of these pathogens. Studies from our laboratory have reported that the pathogens induce a rapid intraepithelial lymphocyte (IEL) response important for host protection. Although mucosal dendritic cells (DC) are likely involved in triggering an antigen-specific IEL response, the specific subset(s) responsible has yet to be identified. Toward this goal, we demonstrate a very important role for mucosal CD11b ؊ CD8 ؉ DC in the initiation of an antigen-specific IEL in vivo. Effectively, after Encephalitozoon cuniculi infection, CD11b؊ CD8 ؉ DC were activated in the lamina propria (LP) and acquired the ability to process retinoic acid (RA). However, this subset did not produce interleukin 12 (IL-12) but upregulated CD103, which is essential for migration to the mesenteric lymph nodes (MLN). Interestingly, CD103؉ CD11b ؊ CD8 ؉ DC in the MLN, in addition to processing RA, also secreted IL-12 and were responsible for gut imprinting specificity on mucosal CD8 T cells. To the best of our knowledge, this is the first report describing the importance of MLN CD103 ؉ CD11b ؊ CD8 ؉ DC isolated from infected animals in the generation of an IEL response against a live pathogen. Human microsporidiosis is an opportunistic infection caused by a spore-forming unicellular eukaryote related to fungi, most specifically zygomycetes (1). Of the 14 species infecting humans, Enterocytozoon bieneusi, Encephalitozoon intestinalis, Encephalitozoon cuniculi, and Encephalitozoon hellem are the most common (2). The incidence of microsporidia in HIV patients remains very high, especially in places such as Russia, Venezuela, and Thailand, where microsporidium prevalence ranges from 13 to 80% (3-5). Lately, it has been reported that microsporidial infections can cause complications in non-HIV populations, especially those receiving organ transplants (6-9). In a very recent study, Kotkova et al. demonstrated that microsporidiosis was probably a latent infection, which could reactivate in an immunocompromised situation, further highlighting the importance of studying the immune response against this ubiquitous pathogen (10). An experimental murine model using E. cuniculi mimics the human infection and has commonly been used to investigate the host immune response (11). Most microsporidial species are acquired by ingesting contaminated water or food, and the gut immunity to this pathogen still remains cryptic. Intraepithelial lymphocytes (IEL) form one of the first lines of immune defense in the gut tissue (12), and their protective role against various pathogens has been reported (13-16). Previous studies from our laboratory demonstrated early and rapid induction of th...

Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

“…Therefore, we first hypothesized that Y. pseudotuberculosis indirectly affects T cell differentiation via modulation of DC subsets within mLNs. Indeed, the strongly decreased frequency of tolerogenic CD103 + CD8 + DCs could account for reduced Treg induction [ 23 , 24 , 38 ], although it cannot be formally excluded that the reduced frequency of CD103 − CD8 + DCs, which most probably belong to resident DCs [ 27 ] and for which a tolerogenic phenotype has been described before [ 39 ], are also responsible. In contrast, expansion of the CD103 DC subset might be responsible for increased differentiation of Th17 cells [ 24 , 40 ].…”

Mechanisms by which gut microorganisms influence food sensitivities

“…Intestinal inflammation abrogates the ability of CD103 + DCs to promote pT reg cell differentiation 168 , and under tissue distress, such as dermal parasitic Leishmania major infection, the CD103 + CD11b − DC subset was shown to produce IL-12 and to drive T H 1 cell immunity in mice 166 . Similarly, fungal infection with Encephalitozoon cuniculi induced a pro-inflammatory programme in lamina propria-residing, IL-12-producing CD103 + CD11b − CD8 + DCs in mice 169 . This finding is in accordance with a study showing that enteric type 1 strain Lang (T1L) reovirus infection 5 induced pro-inflammatory IL-12 production by mucosal CD103 + CD11b − DCs, which drove T H 1 cell responses to the dietary antigen gluten in an IRF1-dependent manner in animal models.…”

Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes

“…For example, lamina propria DCs constitutively produce retinoid acid and TGF-β, which induce gut-homing and differentiation of induced iIELs (143–146). DCs also are important for presenting antigens to induced TCRαβ + iIELs (147, 148). In human celiac disease, anti-gluten CD4 + T cells in the lamina propria contribute to activation of induced CD8αβ + TCRαβ + iIELs (149).…”