Publications by authors named "Juan Carlos Yam-Puc"

14 Publications

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Enhanced BCR signaling inflicts early plasmablast and germinal center B cell death.

iScience 2021 Feb 7;24(2):102038. Epub 2021 Jan 7.

Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK.

It is still not clear how B cell receptor (BCR) signaling intensity affects plasma cell (PC) and germinal center (GC) B cell differentiation. We generated Cγ1 Ptpn6 mice where SHP-1, a negative regulator of BCR signaling, is deleted rapidly after B cell activation. Although immunization with T-dependent antigens increased BCR signaling, it led to PC reduction and increased apoptosis. Dependent on the antigen, the early GC B cell response was equally reduced and apoptosis increased. At the same time, a higher proportion of GC B cells expressed cMYC, suggesting GC B cell-Tfh cell interactions may be increased. GC B cell numbers returned to normal at later stages, whereas affinity maturation was suppressed in the long term. This confirms that BCR signaling not only directs affinity-dependent B cell selection but also, without adequate further stimulation, can inflict cell death, which may be important for the maintenance of B cell tolerance.
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http://dx.doi.org/10.1016/j.isci.2021.102038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822941PMC
February 2021

Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells.

Front Oncol 2020 15;10:587809. Epub 2021 Jan 15.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Gaining knowledge of the neoplastic side of the three main cells-B cells, Follicular Helper T (Tfh) cells, and follicular dendritic cells (FDCs) -involved in the germinal center (GC) reaction can shed light toward further understanding the microuniverse that is the GC, opening the possibility of better treatments. This paper gives a review of the more complex underlying mechanisms involved in the malignant transformations that take place in the GC. Whilst our understanding of the biology of the GC-related B cell lymphomas has increased-this is not reviewed in detail here-the dark side involving neoplasms of Tfh cells and FDCs are poorly studied, in great part, due to their low incidence. The aggressive behavior of Tfh lymphomas and the metastatic potential of FDCs sarcomas make them clinically relevant, merit further attention and are the main focus of this review. Tfh cells and FDCs malignancies can often be misdiagnosed. The better understanding of these entities linked to their molecular and genetic characterization will lead to prediction of high-risk patients, better diagnosis, prognosis, and treatments based on molecular profiles.
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http://dx.doi.org/10.3389/fonc.2020.587809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843373PMC
January 2021

Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

Cell Rep 2020 11;33(5):108328

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address:

Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.108328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653457PMC
November 2020

Langerhans Cells From Mice at Birth Express Endocytic- and Pattern Recognition-Receptors, Migrate to Draining Lymph Nodes Ferrying Antigen and Activate Neonatal T Cells .

Front Immunol 2020 27;11:744. Epub 2020 Apr 27.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN, Mexico City, Mexico.

Antigen capturing at the periphery is one of the earliest, crucial functions of antigen-presenting cells (APCs) to initiate immune responses. Langerhans cells (LCs), the epidermal APCs migrate to draining lymph nodes (DLNs) upon acquiring antigens. An arsenal of endocytic molecules is available to this end, including lectins and pathogen recognition receptors (PRRs). However, cutaneous LCs are poorly defined in the early neonatal period. We assessed endocytic molecules expression : Mannose (CD206)-, Scavenger (SRA/CD204)-, Complement (CD2l, CDllb)-, and Fc-Receptors (CD16/32, CD23) as well as CD1d, CD14, CD205, Langerin (CD207), MHCII, and TLR4 in unperturbed epidermal LCs from both adult and early neonatal mice. As most of these markers were negative at birth (day 0), LC presence was revealed with the conspicuous, epidermal LC-restricted ADPase (and confirmed with CD45) staining detecting that they were as numerous as adult ones. Unexpectedly, most LCs at day 0 expressed CD14 and CD204 while very few were MHCII+ and TLR4+. In contrast, adult LCs lacked all these markers except Langerin, CD205, CD11b, MHCII and TLR4. Intriguingly, the CD204+ and CD14+ LCs predominant at day 0, apparently disappeared by day 4. Upon cutaneous FITC application, LCs were reduced in the skin and a CD204+MHCII+FITC+ population with high levels of CD86 subsequently appeared in DLNs, with a concomitant increased percentage of CD3+CD69+ T cells, strongly suggesting that neonatal LCs were able both to ferry the cutaneous antigen into DLNs and to activate neonatal T cells . Cell cycle analysis indicated that neonatal T cells in DLNs responded with proliferation. Our study reveals that epidermal LCs are present at birth, but their repertoire of endocytic molecules and PRRs differs to that of adult ones. We believe this to be the first description of CDl4, CD204 and TLR4 in neonatal epidermal LCs . Newborns' LCs express molecules to detect antigens during early postnatal periods, are able to take up local antigens and to ferry them into DLNs conveying the information to responsive neonatal T cells.
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http://dx.doi.org/10.3389/fimmu.2020.00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197463PMC
March 2021

Intestinal CD103CD11b cDC2 Conventional Dendritic Cells Are Required for Primary CD4 T and B Cell Responses to Soluble Flagellin.

Front Immunol 2018 17;9:2409. Epub 2018 Oct 17.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Systemic immunization with soluble flagellin (sFliC) from Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103CD11b cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4 T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and mice (which have reduced numbers of cDC2, particularly intestinal CD103CD11b cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103CD11b cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103CD11b cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103CD11b cDC2 in the induction of Th2-associated responses. mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103CD11b cDC2.
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http://dx.doi.org/10.3389/fimmu.2018.02409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199373PMC
October 2019

Evaluating the IgMi mouse as a novel tool to study B-cell biology.

Eur J Immunol 2018 12 26;48(12):2068-2071. Epub 2018 Oct 26.

Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science centre, The University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland.

The IgMi mouse fails to secrete antibodies or class switch its BCR from IgM. Our study reveals that other cellular compartments, including B-cell subsets, DC subsets, GC B cells and T cells are perturbed in the IgMi mouse, thus presenting important additional considerations when using the mouse to explore the role of secreted antibody.
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http://dx.doi.org/10.1002/eji.201847735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750126PMC
December 2018

Role of B-cell receptors for B-cell development and antigen-induced differentiation.

F1000Res 2018 6;7:429. Epub 2018 Apr 6.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

B-cell development is characterized by a number of tightly regulated selection processes. Signals through the B-cell receptor (BCR) guide and are required for B-cell maturation, survival, and fate decision. Here, we review the role of the BCR during B-cell development, leading to the emergence of B1, marginal zone, and peripheral follicular B cells. Furthermore, we discuss BCR-derived signals on activated B cells that lead to germinal center and plasma cell differentiation.
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http://dx.doi.org/10.12688/f1000research.13567.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893946PMC
April 2018

Corrigendum: Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2017 12;8:440. Epub 2017 Apr 12.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, Instituto Politécnico Nacional (IPN) , Mexico City , Mexico.

[This corrects the article on p. 396 in vol. 7, PMID: 27746783.].
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http://dx.doi.org/10.3389/fimmu.2017.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388691PMC
April 2017

Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult.

Front Immunol 2017 19;8:13. Epub 2017 Jan 19.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Lymph nodes (LNs) have evolved to maximize antigen (Ag) collection and presentation as well as lymphocyte proliferation and differentiation-processes that are spatially regulated by stromal cell subsets, including fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs). Here, we showed that naïve neonatal mice have poorly organized LNs with few B and T cells and undetectable FDCs, whereas adult LNs have numerous B cells and large FDC networks. Interestingly, immunization on the day of birth accelerated B cell accumulation and T cell recruitment into follicles as well as FDC maturation and FRC organization in neonatal LNs. However, compared to adults, the formation of germinal centers was both delayed and reduced following immunization of neonatal mice. Although immunized neonates poorly expressed activation-induced cytidine deaminase (AID), they were able to produce Ag-specific IgGs, but with lower titers than adults. Interestingly, the Ag-specific IgM response in neonates was similar to that in adults. These results suggest that despite an accelerated structural maturation of LNs in neonates following vaccination, the B cell response is still delayed and reduced in its ability to isotype switch most likely due to poor AID expression. Of note, naïve pups born to Ag-immunized mothers had high titers of Ag-specific IgGs from day 0 (at birth). These transferred antibodies confirm a mother-derived coverage to neonates for Ags to which mothers (and most likely neonates) are exposed, thus protecting the neonates while they produce their own antibodies. Finally, the type of Ag used in this study and the results obtained also indicate that T cell help would be operating at this stage of life. Thus, neonatal immune system might not be intrinsically immature but rather evolutionary adapted to cope with Ags at birth.
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http://dx.doi.org/10.3389/fimmu.2017.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243854PMC
January 2017

Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2016 29;7:396. Epub 2016 Sep 29.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, National Polytechnic Institute , Mexico City , Mexico.

Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus. Of note, anti-NPA antibodies are also detected in patients with SLE and leprosy. We used this model of lupus to investigate the cellular mechanisms that lead to the production of anti-lipid, class-switched IgG antibodies. In this murine lupus model, we found plasma cells (Gr1, CD19, CD138) producing NPA-specific IgGs in the draining lymph nodes, the spleen, and the bone marrow. We also found a significant number of germinal center B cells (IgD, CD19, PNA) specific for NPA in the draining lymph nodes and the spleen, and we identified the presence of NPA in these germinal centers. By contrast, very few NPA-specific, extrafollicular reaction B cells (B220, Blimp1) were found. Moreover, when assessing the anti-NPA IgG antibodies produced during the experimental protocol, we found that the affinity of these antibodies progressively increased over time. Altogether, our data indicate that, in this murine model resembling human lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.
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http://dx.doi.org/10.3389/fimmu.2016.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040728PMC
September 2016

The Cellular Bases of Antibody Responses during Dengue Virus Infection.

Front Immunol 2016 6;7:218. Epub 2016 Jun 6.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated.
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http://dx.doi.org/10.3389/fimmu.2016.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893500PMC
July 2016

Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.

Eur J Immunol 2015 Aug 24;45(8):2299-311. Epub 2015 Jun 24.

Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.

Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T-bet(+) IFN-γ(+) CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B-cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL-4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL-12 and TNFα expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naïve T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection-induced, Th1-mediated inflammation.
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http://dx.doi.org/10.1002/eji.201545564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973836PMC
August 2015

Germinal center reaction following cutaneous dengue virus infection in immune-competent mice.

Front Immunol 2015 24;6:188. Epub 2015 Apr 24.

Department of Cell Biology, Center for Advanced Research, National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Dengue virus (DENV) has four serotypes, which can cause from asymptomatic disease to severe dengue. Heterologous secondary infections have been associated to a greater risk of potentially fatal dengue due to non-neutralizing memory antibodies (Abs), which facilitate the infection, such as anti-precursor membrane (prM) Abs, among other mechanisms. Usually, class-switched memory Abs are generated mainly through germinal centers (GCs). However, the cellular events underlying these Ab responses to DENV, especially during repeated/secondary infections, have been poorly studied. We wanted to know whether there is involvement of GC reactions during cutaneous DENV infection and whether there is any sort of preferential Ab responses to defined viral proteins. Intradermal DENV inoculation at a relatively low dose efficiently infects immune-competent BALB/c mice, inducing higher quantities of DENV-specific GC B cells and larger GCs than the control conditions. Interestingly, GCs exhibited as much prM as envelope (E) and non-structural 3 viral proteins in situ. Intriguingly, despite the much larger abundance of E protein than of prM protein in the virions, infected animals showed similar amounts of circulating Abs and Ag-specific GC B cells both for prM and for E proteins, even significantly higher for prM. To the best of our knowledge, there are no reports of the GC responses during DENV infection. This relatively stronger anti-prM response could be triggered by DENV to preferentially promote Abs against certain viral proteins, which might favor infections by facilitating DENV invasion of host cells. It is thus conceivably that DENV might have evolved to induce this kind of Ab responses.
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http://dx.doi.org/10.3389/fimmu.2015.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408864PMC
May 2015

Germinal center reaction following cutaneous dengue virus infection in immune-competent mice.

Front Immunol 2015 24;6:188. Epub 2015 Apr 24.

Department of Cell Biology, Center for Advanced Research, National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Dengue virus (DENV) has four serotypes, which can cause from asymptomatic disease to severe dengue. Heterologous secondary infections have been associated to a greater risk of potentially fatal dengue due to non-neutralizing memory antibodies (Abs), which facilitate the infection, such as anti-precursor membrane (prM) Abs, among other mechanisms. Usually, class-switched memory Abs are generated mainly through germinal centers (GCs). However, the cellular events underlying these Ab responses to DENV, especially during repeated/secondary infections, have been poorly studied. We wanted to know whether there is involvement of GC reactions during cutaneous DENV infection and whether there is any sort of preferential Ab responses to defined viral proteins. Intradermal DENV inoculation at a relatively low dose efficiently infects immune-competent BALB/c mice, inducing higher quantities of DENV-specific GC B cells and larger GCs than the control conditions. Interestingly, GCs exhibited as much prM as envelope (E) and non-structural 3 viral proteins in situ. Intriguingly, despite the much larger abundance of E protein than of prM protein in the virions, infected animals showed similar amounts of circulating Abs and Ag-specific GC B cells both for prM and for E proteins, even significantly higher for prM. To the best of our knowledge, there are no reports of the GC responses during DENV infection. This relatively stronger anti-prM response could be triggered by DENV to preferentially promote Abs against certain viral proteins, which might favor infections by facilitating DENV invasion of host cells. It is thus conceivably that DENV might have evolved to induce this kind of Ab responses.
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http://dx.doi.org/10.3389/fimmu.2015.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408864PMC
May 2015