Changes in maternal immunity during pregnancy can result in an altered immune state and, as a natural perturbation, this provides an opportunity to understand functional interactions of the immune system in vivo. We report characterisation of maternal peripheral immune phenotypes for 33 longitudinally sampled normal pregnancies, using clinical measurements of complete blood counts and major immune cell populations, as well as high parameter flow cytometry for 30 different leukocyte antigens characterising 79 cell populations, and monitoring of 1305 serum proteins using the SomaLogic platform. Cellular analyses characterised transient changes in T cell polarization, and more persistent alterations in T and B cell subset frequencies and activation. Serum proteomic analysis identified a novel set of 7 proteins that are predictive of gestational age: DDR1, PLAU, MRC1, ACP5, ROBO2, IGF2R, and GNS. We further show that gestational age can be predicted from the parameters obtained by complete blood count tests and clinical flow cytometry characterizing 5 major immune cell populations. Inferring gestational age from this routine clinical phenotyping data could be useful in resource limited settings which lack obstetric ultrasound. Overall, both the cellular and proteomic analyses validate previously reported phenotypic immunological changes of pregnancy, and uncover new alternations and predictive markers.
Richard Apps, Yuri Kotliarov, Foo Cheung, Kyu Lee Han, Jinguo Chen, Angelique Biancotto, Ashley L. Babyak, Huizhi Zhou, Rongye Shi, Lisa A. Barnhart, Sharon M. Osgood, Yasmine Belkaid, Steven M. Holland, John S. Tsang, Christa Zerbe
Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro–activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.
Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos
Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%–90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.
Emmanuel Martin, Norbert Minet, Anne-Claire Boschat, Sylvia Sanquer, Steicy Sobrino, Christelle Lenoir, Jean Pierre de Villartay, Maria Leites-de-Moraes, Capucine Picard, Claire Soudais, Tim Bourne, Sophie Hambleton, Stephen M. Hughes, Robert F. Wynn, Tracy A. Briggs, Genomics England Research Consortium, Smita Patel, Monica G. Lawrence, Alain Fischer, Peter D. Arkwright, Sylvain Latour
Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6–7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb–infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb-infected T2DM mice compared with Mtb-infected nondiabetic mice. BCG vaccination significantly reduced lung inflammation in Mtb-infected T2DM mice compared with that of unvaccinated T2DM mice infected with Mtb. Furthermore, reduced mortality of BCG-vaccinated Mtb-infected T2DM mice is associated with expansion of IL-13–producing CXCR3+ Tregs in the lungs of Mtb-infected T2DM mice. Recombinant IL-13 and Tregs from BCG-vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages to antiinflammatory M2 macrophages. Our findings suggest a potentially novel role for BCG in preventing excess inflammation and mortality in T2DM mice infected with Mtb.
Rajesh Kumar Radhakrishnan, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline Kay McAllister, Sachin Mulik, Buka Samten, Ramakrishna Vankayalapati
Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell–mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ–producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.
Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin
CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor–dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
Ugur Eskiocak, Wilson Guzman, Benjamin Wolf, Christine Cummings, Lauren Milling, Hsin-Jung Wu, Michael Ophir, Conner Lambden, Pearl Bakhru, Dana C. Gilmore, Samantha Ottinger, Lucy Liu, William K. McConaughy, Sunny Q. He, Chao Wang, Cheuk Lun Leung, Jason Lajoie, William F. Carson IV, Nora Zizlsperger, Michael M. Schmidt, Ana C. Anderson, Piotr Bobrowicz, Thomas J. Schuetz, Robert Tighe
Chikungunya virus (CHIKV) infection causes acute febrile illness in humans and some of these individuals develop a debilitating chronic arthritis that can persist for months to years for reasons that remain poorly understood. In this study from India, we characterized antibody response patterns in chikungunya febrile patients and further assessed the association of these initial febrile phase antibody response patterns with protection versus progression to developing chronic arthritis. We found five distinct patterns of the antibody responses in febrile phase: No CHIKV binding or Neutralizing (NT) antibodies but PCR positive, IgM alone with no NT activity, IgM alone with NT activity, IgM and IgG without NT activity, IgM and IgG with NT activity. A 20-month follow-up showed that appearance of NT activity regardless of antibody isotype or appearance of IgG regardless of NT activity during the initial febrile phase is associated with a robust protection against developing chronic arthritis in the future. These findings, while providing novel insights on correlates of protective immunity against chikungunya-induced chronic arthritis, suggest that qualitative differences in the antibody response patterns that have evolved during the febrile phase can serve as biomarkers, that allow prediction of protection or progression to chronic arthritis in the future.
Kaustuv Nayak, Vineet Jain, Manpreet Kaur, Naushad Khan, Kamalvishnu Gottimukkala, Charu Aggarwal, Rohit Sagar, Shipra Gupta, Ramesh Chandra Rai, Kritika Dixit, Mohammad Islamuddin, Anil Verma, Deepti Maheshwari, Yadya M. Chawla, Elluri Seetharami Reddy, Harekrushna Panda, Pragati Sharma, Priya Bhatnagar, Prabhat Singh, Siva Raghavendhar, Ashok Kumar Patel, Vinod H. Ratageri, Anmol Chandele, Pratima Ray, Kaja Murali-Krishna
Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ–JAK1/2–STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus–infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.
Teresa Preglej, Patricia Hamminger, Maik Luu, Tanja Bulat, Liisa Andersen, Lisa Göschl, Valentina Stolz, Ramona Rica, Lisa Sandner, Darina Waltenberger, Roland Tschismarov, Thomas Faux, Thorina Boenke, Asta Laiho, Laura L. Elo, Shinya Sakaguchi, Günter Steiner, Thomas Decker, Barbara Bohle, Alexander Visekruna, Christoph Bock, Birgit Strobl, Christian Seiser, Nicole Boucheron, Wilfried Ellmeier
Neutrophils are the most abundant inflammatory cells at the earliest stages of wound healing and play important roles in wound repair and fibrosis. Formyl peptide receptor 1 (FPR-1) is abundantly expressed on neutrophils and has been shown to regulate their function, yet the importance of FPR-1 in fibrosis remains ill defined. FPR-1–deficient (fpr1–/–) mice were protected from bleomycin-induced pulmonary fibrosis but developed renal and hepatic fibrosis normally. Mechanistically, we observed a failure to effectively recruit neutrophils to the lungs of fpr1–/– mice, whereas neutrophil recruitment was unaffected in the liver and kidney. Using an adoptive transfer model we demonstrated that the defect in neutrophil recruitment to the lung was intrinsic to the fpr1–/– neutrophils, as C57BL/6 neutrophils were recruited normally to the damaged lung in fpr1–/– mice. Finally, C57BL/6 mice in which neutrophils had been depleted were protected from pulmonary fibrosis. In conclusion, FPR-1 and FPR-1 ligands are required for effective neutrophil recruitment to the damaged lung. Failure to recruit neutrophils or depletion of neutrophils protects from pulmonary fibrosis.
Jack Leslie, Ben J.M. Millar, Alicia del Carpio Pons, Rachel A. Burgoyne, Joseph D. Frost, Ben S. Barksby, Saimir Luli, Jon Scott, A. John Simpson, Jack Gauldie, Lynne A. Murray, Donna K. Finch, Alan M. Carruthers, John Ferguson, Matthew A. Sleeman, David Rider, Rachel Howarth, Christopher Fox, Fiona Oakley, Andrew J. Fisher, Derek A. Mann, Lee A. Borthwick
The specificity of antibodies (Abs) generated to influenza A virus (IAV) infection can significantly alter protection and viral clearance. At present, the impact of age upon this process is relatively unexplored. Here, we evaluated the Ab response in newborn and adult African green monkeys (AGM) following infection with IAV using a strain that enables us to determine the immunodominance (ID) hierarchy of the Ab response to hemagglutinin (HA), the principal target of protective Abs. This revealed altered ID patterns in the early IgM anti-HA response in newborns versus adults that converged over time. While the IgG ID profiles for HA in newborn and adult monkeys were similar, this was not the case for IgA. Importantly, HA stem-specific Abs were generated robustly and similarly in newborns and adults in terms of quality and quantity. Together these results demonstrate that newborns and adults can differ in the Ab ID pattern established following infection and that the ID pattern can vary across isotypes. In addition, newborns have the ability to generate potent HA stem-specific Ab responses. Our findings further the understanding of the newborn response to IAV antigens and inform the development of improved vaccines for this at-risk population.
Elene A. Clemens, Davide Angeletti, Beth C. Holbrook, Masaru Kanekiyo, Matthew J. Jorgensen, Barney S. Graham, Jonathan W. Yewdell, Martha A. Alexander-Miller
No posts were found with this tag.