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Meeting report - Keystone Symposia meeting on B Cell Renaissance

Here is the meeting report written by Sébastien This, laureate of the CFCD travel award for the Keystone Symposia meeting on B Cell Renaissance: Epigenetics, Regulation and Immunotherapy.

Xcr1+ dendritic cells are necessary for the formation of tolerant CD4 T cells induced by chemically-fixed antigen-coupled splenocytes
Justin A. Spanier1, James R. Heffernan1, Jason S. Mitchell1, Kevin C. Osum1, Jenna L. Ruggiero1, Milcah C. Scott1, Nathanael L. Sahli1, Brian T. Fife1,
1 University of Minnesota, Center for Immunology, Minneapolis, MN, USA

The authors of this study investigate strategies to induce tolerogenic T cells to self or self-associated antigens in the context of the autoimmune Type 1 diabetes (T1D) disease. Using the BDC2.5 TCR transgenic mouse model, spontaneously developing T1D, the authors describe a method for hijacking conventional dendritic cell (cDC) to generate tolerogenic CD4+ T cells and induce tolerance to T1D.
The use of the chemical cross linker 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC) allows to coat self-antigen (p31 peptide here) at the surface of apoptotic lymphocytes. Injection of these lymphocytes induces strong protection to the BDC2.5 mediated T1D induction.
Investigating the mechanisms of tolerance induction, the authors showed that CD8α+Xcr1+ DCs preferentially engulfed apoptotic cells, resulting in a rapid increase in MHCII expression. These cellular interactions were required for self-tolerance and promoted stable contacts with BDC2.5 CD4+ T cells in a peptide:MHCII-dependent manner. Furthermore, depletion of Xcr1-expressing DCs using Diphtheria Toxin in NOD.XCR1-DTR transgenic mice abrogated tolerance induction.
Investigating the phenotype of tolerant BDC2.5 CD4 cell being generated following Antigen-coupled splenoncytes injection, the authors used RNA sequencing to compare these cell to the effector BDC2.5 CD4 Th1 cells. They find that tolerant BDC2.5 CD4 T cells upregulated genes associated with exhausted T cells (LAG3, TIM3 and BTLA), and T follicular helper cells (IL-21, ICOS, CXCR5 and PD-1).
Overall, these results suggest that XCR1+ DC, in response to EDC fixed antigen-coated apoptotic cells, reprogram effector CD4 T cells into tolerant cells, potentially through expression networks that are shared among other T cell subsets with poor inflammatory effector potential.
They author propose that this technique could be used to improve existing tolerance-promoting therapies and promote the non-responsiveness of self-antigen specific effector T to ultimately treat or prevent autoimmune disorders.

Thymic B Cells and T Cell Tolerance
Haochu Huang 1, 2
1 Committee on Immunology, Department of Medicine, and Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
2 Current address: Department of Translational Oncology, Genentech, South San Francisco, California, USA

The authors present a population of B cells found in the medullary region of the thymus that colocalize with dendritic cells and medullary thymic epithelial cells. The authors investigated the origin and role of these thymic B cells which is not well understood.
Using a model of parabiotic mice, the authors demonstrate that while a small fraction of thymic B cells arise from the blood, the vast majority develop from progenitors within the thymus.
Furthermore, thymic B cells express high levels of MHC class II and show activated phenotypes. Given their superior ability for presenting antigens that are recognized by B cell receptors, the author demonstrate that autoreactive thymic B cells can be efficient antigen-presenting cells for T cell negative selection. The exact antigens presented by these particular B cells are not known but the author speculate that these antigens might be BCR antigens or B cell specific antigens. These B cells express the AIRE molecule allowing them to present self and self associated-peptides
Interestingly a large percentage of thymic B cells undergo class switching and thymic B cell class switching to IgG2b, IgG2c and IgA which is dependent on the cognate interaction with specific T cells. Furthermore, class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Autoreactive B cell preferentially expand in the thymus and undergo class switching. This study provide a very interesting novel mechanism for myeloid cell-independent autoreactive T cell selection in the Thymus. This process is an interesting negative-feedback mechanism to purge autoreactive T cells that could drive autoreactive B cells to autoimmunity.

Microbiota-induced regulatory T cells induce a localized block in intestinal CD4 T cell responses to oral vaccination

Amrita Bhattacharjee1, Justin T. Tometich1, Abigail E. Overacre-Delgoffe1, Ansen H.P. Burr1, Sean P. Spencer2, Jonathan L. Linehan2, Junyi Ji1, Denise Morais da Fonseca2, Yasmine Belkaid2, Timothy W. Hand
1 R. K. Mellon Institute, Dept. of Pediatrics, UPMC Children's Hospital, Univ. of Pittsburgh
2 Metaorganism Immunity Section, Laboratory of Systems Biology, NIAID/NIH

The authors are interested in understanding the mechanisms by which Environmental Enteric Dysfunction affect the intestinal immune system. Environmental Enteric Dysfunction (EED) affects millions of children worldwide, leading to stunted growth and intellectual development. EED induces a dysfunction intestinal immune system that is associated with malnutrition and intestinal infection, leading to intestinal damage, microbiome dysbiosis and reduced absorption. Furthermore, EED is also associated with a reduced efficacy of oral vaccines, limiting the protection of children against chronic enteric infection.
The authors develop a model of EED in mice driven by a low protein and high fat diet in addition to non-pathogenic E. coli infection (low grade irritation) mimicking the human disease. These mice display delayed growth, high intestinal damage at the cellular level and blunted intestinal immune responses.
In particular the authors use a model of oral vaccination with an attenuated E. coli labile toxin (dmLT) which generates strong TH1 and TH17 responses in the intestinal lamina propria. EED mice display reduced effector TH17 and TH1 responses restricted to the intestinal tissues as no difference could be found in the mesenteric lymph nodes.
The authors showed that this was associated to a higher frequency of RORt+FoxP3+ TREG in EED mice. Deletion of the intestinal TREG restored intestinal LT-specific CD4+ T cell responses. Furthermore, induction of EED in IL10 deficient mice resulted in a more severe disease.
Taken together, the authors have shown that, in the context of EED, a shift in the intestinal microbiota associated with chronic inflammation can lead to a localized blockade of T cell immunity by RORt+FoxP3+ induced TREG , that leaves systemic immunity intact. This local increased TREG frequency in the intestinal lamina propria is furthermore responsible for the decrease efficacy of mucosal vaccination in the EED mice.  

Intestinal IgA Response to Infection from the Macrophage Perspective
Balázs Koscsó, Sravya Kurapati, Richard R Rodrigues, Kavitha Gowda, Jelena Nedjic, Changsik Shin, Chetna Soni, Indira Purushothaman, Maryknoll Palisoc, Sulei Xu, Haoyu Sun, Sathi Babu Chodisetti, Eugene Lin, Matthias Mack, Yuka Imamura Kawasawa, Pingnian He, Ziaur S.M. Rahman, Iannis Aifantis, Natalya Shulzhenko, Andriy Morgun, Milena Bogunovic.
University of Massachusetts Medical School, Worcester, MA

The authors investigate antigen-presenting cell types that initiate the Salmonella-specific mucosal IgA response. Intestinal antigen-presenting cells are represented by conventional dendritic cell and macrophage subsets that together with monocytes derived phagocytes form the large majority of intestinal antigen presenting cells (APC).
The authors performed phenotypical, transcriptional, and functional analyses of inflammatory APC in infectious (wild type Salmonella) driven colitis. They identified CX3CR1+ APC as the most prevalent inflammatory cell type following Salmonella infection. RNA sequencing of these cells revealed that they are transcriptionally aligned with macrophages and derive from blood monocytes.
The authors further demonstrate that mucosal resident CX3CR1+ macrophages are superior to cDC1 and cDC2 in vivo in inducing Salmonella-specific mucosal IgA. CX3CR1hi macrophages expressed the highest levels of genes encoding anti-inflammatory cytokines (Il10 and Tgfb1) and showing the strongest signature for genes involved in the induction of B cell and IgA responses. This local IgA response develops independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total IgA response to infection, this suggesting that they induce immune responses locally within the mucosa.
This work highlights the importance of taking into account for the heterogeneous intestinal macrophages subsets when studying mucosal IgA responses. This study complements very nicely the studies implicating Peyer’s Patches cDC2 and Mesenteric Lymph nodes cDC1 in the regulation of IgA responses to commensal microbiota and rotavirus respectively. This study thus further confirms the notion that the nature of the trigger and the organs in which this response is initiated is critical in determining which APC will be most critical for IgA induction.

Novel specialized cell state and spatial compartments within the germinal center
Domenick E Kennedy1, Michael K Okoreeh1, Mark Maienschein-Cline2, Junting Ai1, Margaret Veselits1, Kaitlin C McLean1, Yogesh Dhugana3, Hong Wang4,5, Junmin Peng4,5, Hongbo Chi3, Malay Mandal1, Marcus R Clark1
1 Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago 60637, Illinois, USA.
2 Core for Research Informatics, University of Illinois at Chicago, Chicago 60612, Illinois, USA.
3 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
4 Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
5 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA

GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. Using the CXCR4 and CD83 markers, the authors further separate the GC in 3 populations : the LZ, DZ and Grey Zone (GZ) which they define as CXCR4hiCD83hi. These GZ B cells represent a novel population within the canonical DZ B cell population, have been shown to localize within the canonical DZ compartment and represent the dividing population of DZ B cells.
Using many multidimensional analyses, including ATAC-Seq, RNA-Seq, single cell RNA-Seq, proteome and phosphoproteome, the authors show that these 3 newly described subsets display distinct molecular programs in each population which correlated with their observed functions.
Altogether these data provide a new model for how GC B cells cycle during the GC reaction. Upon encounter with the antigen, B cells proliferate into the GZ which is critical for the amplification of the humoral response. In the GZ, the authors show that these B cell interact with tingible body macrophages (TBM). The function of TBM is still poorly known and the author show a potential role for the support of GC B cell proliferation. Upon egress for the GC, these cells express the AID molecule and undergo somatic hypermutation. These differentiating (DZd) cells then migrate to the light zone for differentiation.
This study provides a new three-cell population GC model that separates division, SHM and selection into distinct compartments and provide a better understanding of GC function and potential regulation. This study also provides a framework for better understanding the molecular and cellular regulation of the diverse B cell processes, a an transcription, epigenetic and proteomic level.