Mice lacking all conventional MHC class II genes

Madsen, Lars Siim; Labrecque, Nathalie; Engberg, Jan; Dierich, Andrée; Svejgaard, A.; Benoist, Christophe; Mathis, Diane; Fugger, Lars

doi:10.1073/pnas.96.18.10338

Cited by 298 publications

(284 citation statements)

References 35 publications

(28 reference statements)

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“…1 and 2A), in agreement with a previous report that analyzed lymphocyte numbers in the spleen and LNs in mice of the same genotype [27]. This impairment is likely the consequence of a lack of thymic selection in these mice, which results in an imbalanced CD8 + /CD4 + T-cell ratio.…”

Section: Mhcii Is Necessary For Early Mucosal Th17 Responses To C Rosupporting

confidence: 80%

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

et al. 2013

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The enteric pathogen Citrobacter rodentium induces a mucosal IL-17 response in CD4 + T helper (Th17) cells that is dependent on the Nod-like receptors Nod1 and Nod2. Here, we sought to determine whether this early Th17 response required antigen presentation by major histocompatibility complex class II (MHCII) for full induction. At early phases of C. rodentium infection, we observed that the intestinal mucosal Th17 response was fully blunted in irradiated mice reconstituted with MHCII-deficient (MHCII −/− →WT) hematopoietic cells. Surprisingly, we also observed a substantial increase in the relative frequency of IL-17 + CD8 + CD4 − TCR-β + cells (Tc17 cells) and FOXP3 + CD8 + CD4 − TCR-β + cells in the lamina propria and intraepithelial lymphocyte compartment of MHCII −/− →WT mice compared with that in WT→WT counterparts. Moreover, MHCII −/− →WT mice displayed increased susceptibility, increased bacterial translocation to deeper organs, and more severe colonic histopathology after infection with C. rodentium. Finally, a similar phenotype was observed in mice deficient for CIITA, a transcriptional regulator of MHCII expression. Together, these results indicate that MHCII is required to mount early mucosal Th17 responses to an enteric pathogen, and that MHCII regulates the induction of atypical CD8 + T-cell subsets, such as Tc17 cells and FOXP3 + CD8 + cells, in vivo. Keywords:Citrobacter rodentium r FOXP3 + CD8 + r IL-17 r MHC class II r Tc17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInterleukin (IL)-17A (herein referred to as IL-17) is a cytokine critical for host defense against pathogens at mucosal surfaces. In the gastrointestinal tract, induction of mucosal IL-17 secretion Correspondence: Dr. Stephen E. Girardin e-mail: stephen.girardin@utoronto.ca was shown to be associated with protection against Salmonella enterica serovar Typhymurium [1], Citrobacter rodentium [2], and Helicobacter species [3]. IL-17 exerts its mucosal protection at least in part through an increase of neutrophil recruitment and neutrophil-driven defense mechanisms. In addition, IL-17 acts in concert with IL-22 to enhance epithelial innate functions, such as antimicrobial peptide secretion, mucus secretion, proliferation, and renewal [4,5].IL-17 can be secreted by a number of cell populations, including CD4 + T helper (Th17) cells, γδ T cells, innate lymphoid cells (that C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2896-2906 Immunity to infection 2897 include lymphoid tissue inducer cells) and natural killer T (NKT) cells [6][7][8][9][10][11]. In humans, Th17 cells appear to represent the major cell population that produces IL-17 in the intestine under normal conditions, whereas in mice IL-17 is mainly produced by Th17 and γδ T cells. Th17 cell differentiation is mediated by the cytokines IL-6 and TGF-β, whereas IL-23 and IL-1β contribute to the full activation of these cells [6,12,13]. In addition to the c...

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Section: Mhcii Is Necessary For Early Mucosal Th17 Responses To C Rosupporting

confidence: 80%

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

et al. 2013

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“…C57BL/ 6 CD45.1 mice and C57BL/6 CD3ε 2/2 mice were maintained in our own animal facilities under specific pathogen-free conditions. C57BL/6 CD3ε 2/2 mice (26) were crossed with MHC II D/D mice (27) to obtain CD3ε/MHC II double-deficient mice (CD3ε 2/2 II D/D mice) (13). C57BL/6 Foxp3-GFP reporter mice were initially provided by Dr. Bernard Malissen (Centre d'Immunologie de Marseille-Luminy, Marseille, France) (28,29) and maintained in our own animal facilities.…”

Section: Methodsmentioning

confidence: 99%

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

Campion

Pommier²,

Delpoux³

et al. 2012

The Journal of Immunology

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Work over the last decades has led to the identification of the factors that influence the survival and homeostasis of conventional T cells. IL-7 and TCR signaling promote the survival of naive CD4+ and CD8+ T cells in lymphoreplete mice and their proliferation in a lymphopenic environment, whereas survival and homeostatic proliferation of memory CD4+ and CD8+ T cells crucially depend on a combination of IL-7 and IL-15. In contrast, there is little information regarding the factors driving the proliferation of regulatory CD4+ T cells in response to lymphopenia. In this study, we investigated whether regulatory CD4+ T cell proliferation in response to lymphopenia was guided by classical homeostatic resources, such as IL-2, IL-7, or TCR–MHC interactions. Altogether, our data suggest that, although homeostatic proliferation of conventional naive CD4+ T cells is closely related to IL-7 levels, the proliferation of regulatory CD4+ T cells in response to lymphopenia appears to be primarily controlled by IL-2. The capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases or cancer immunotherapy.

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“…I-A␤-deficient (MHC class II-deficient) and CD4-deficient mice were obtained from Taconic (Germantown, NY). I-A/I-E-deficient (MHC class II-deficient) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) (45). Act-mOVA mice (24) were bred to I-A␤-deficient mice to produce Act-mOVA MHC class II-deficient mice.…”

Section: Methodsmentioning

confidence: 99%

MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo

Fischer

Jacovetty

Medeiros

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The role continuous contact with self-peptide/MHC molecules (self ligands) in the periphery plays in the function of mature T cells remains unclear. Here, we elucidate a role for MHC class II molecules in T cell trafficking and antigen responsiveness in vivo. We find that naïve CD4 T cells deprived of MHC class II molecules demonstrate a progressive and profound defect in motility (measured by real-time two-photon imaging) and that these cells have a decreased ability to interact with limiting numbers of cognate antigen-bearing dendritic cells, but they do not demonstrate a defect in their responsiveness to direct stimulation with anti-CD3 monoclonal antibody. Using GST fusion proteins, we show that MHC class II availability promotes basal activation of Rap1 and Rac1 but does not alter the basal activity of Ras. We propose that tonic T cell receptor signaling from self-ligand stimulation is required to maintain a basal state of activation of small guanosine triphosphatases critical for normal T cell motility and that T cell motility is critical for the antigen receptivity of naïve CD4 T cells. These studies suggest a role for continuous self-ligand stimulation in the periphery for the maintenance and function of mature naïve CD4 T cells.GTPases ͉ MHC class II deficiency ͉ self ligand

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Mice lacking all conventional MHC class II genes

Cited by 298 publications

References 35 publications

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo

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