Erica G. Schmitt

St. Louis Children's Hospital

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i-10 index

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Co-Authors

Megan A. Cooper

St. Louis Children's Hospital

Calvin B. Williams

Medical College of Wisconsin

Dipica Haribhai

Medical College of Wisconsin

Nita H. Salzman

Children's Hospital of Wisconsin

Jennifer Ziegelbauer

Versiti Blood Center of Wisconsin

Nermina Saucier

Washington University in St. Louis

Pippa Simpson

Medical College of Wisconsin

Helen C. Su

National Institute of Allergy and Infectious Diseases

Ana Kolicheski

Missouri College

ÉH

Élie Haddad

Centre Hospitalier Universitaire Sainte-Justine

Cooperative Institutions

National and Kapodistrian University of Athens

207

Imperial College London

163

Panagiotis & Aglaia Kyriakou Children's Hospital

162

Patan Academy of Health Sciences

158

Sotiria General Hospital

155

Inserm

122

Rockefeller University

Université Paris Cité

Assistance Publique – Hôpitaux de Paris

Institut des Maladies Génétiques Imagine

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Granzymes are necessary for suppressive function of regulatory T cells

Pediatric Rheumatology (2012)

Dominic O. Co Dipica Haribhai Erica G. Schmitt Jennifer Ziegelbauer William J. Grossman

Purpose Regulatory T (Treg) cells are an essential subset of CD4+ T cells that induce and maintain immunological tolerance. Preclinical animal models have demonstrated that adoptive transfer of Treg cells can prevent or cure diabetes, multiple sclerosis (EAE), inflammatory bowel disease, lupus, arthritis, and graft versus host disease. Defects in Treg cell function and number have been described in a number of different human autoimmune diseases including diabetes, multiple sclerosis, rheumatoid arthritis and juvenile idiopathic arthritis. These data suggest that manipulation of Treg cells may be a useful therapeutic intervention. Treg cells are marked by expression of the forkhead/winged helix transcription factor Foxp3, which is essential for their regulatory functions. Treg cells are well known to mediate their immunomodulatory effects through TGF-b, IL-10 and CTLA-4. Recent work has also suggested a role for the granule/exocytosis pathway in Treg cell suppressive function. Granzyme A and granzyme B (gzm A and gzm B, respectively) mRNAs are expressed at high levels in Treg cells, and Treg cells from gzm B–/– mice showed defects in suppression in vitro. To further examine the role of granzymes in the function of Treg cells in vivo, we used a T cell transfer model of colitis. In this model, naive CD45RBhigh CD4+ T cells transferred to RAG–/– mice and undergo homeostatic expansion and activation.This process results in colitis manifested clinically by weight loss and shortened survival. Previous work has shown that a subset of the transferred conventional T cells develop into Foxp3+ iTreg cells and that these iTreg cells are necessary to mitigate colitis when present together with natural Treg cells (nTreg) cells derived in the thymus. Methods CD45RBhigh T cells from mice expressing a Foxp3EGFP fusion protein and additionally deficient in gzm A or gzm B are transferred to RAG-/mice.In these mice, EGFP expression marks iTreg which have developed in situ. Mice were weighed twice weekly and euthanized when moribund or when they have lost more than 1520% of their initial weight. Mesenteric lymph nodes T cells were analyzed for expression of EGFP.

Granzyme

Adoptive Cell Transfer

10.1186/1546-0096-10-s1-a108

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Novel STAT1 gain-of-function variant in a patient with Bechet’s like clinical phenotype

Clinical Immunology (2023)

Jahnavi Aluri Erica G. Schmitt Ana Kolicheski Matthew Du Nermina Saucier

STAT1

Immunophenotyping

Chronic mucocutaneous candidiasis

10.1016/j.clim.2023.109371

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A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity

Immunity (2011)

Dipica Haribhai Jason B. Williams Shuang Jia Derek W. Nickerson Erica G. Schmitt

Adoptive Cell Transfer

Regulatory T cell

Peripheral tolerance

10.1016/j.immuni.2011.03.029

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Citations (404)

88 Practical Considerations regarding the Immune Dysregulation and Immunodeficiency in Down Syndrome

Clinical Immunology (2024)

Carolyn H. Baloh Melissa Gans Juanita Valdes Camacho Natalia S. Chaimowitz Hanadys Ale

Immune Dysregulation

Primary Immunodeficiency

10.1016/j.clim.2024.110030

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Induced regulatory T cell-derived interleukin 10 is sufficient for the cure of experimental colitis (179.19)

The Journal of Immunology (2012)

Erica G. Schmitt Dipica Haribhai Jason B. Williams Shuang Jia Praful Aggarwal

Abstract Induced Treg (iTreg) cells are essential for tolerance. Although in vitro derived iTreg cells can be used therapeutically in preclinical models of autoimmune disease, their stability in vivo and their mechanisms of suppression have not been examined. Here, we used a treatment model of lymphopenia-associated colitis to examine the role of IL-10 in iTreg cell function. Monotherapy with IL-10-deficient iTreg cells slowed the onset of colitis and decreased colon infiltration, but did not resolve disease. Mice treated with WT iTreg cells in combination with IL-10-deficient natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, indicating that maintenance of the iTreg pool is based on antigen specificity. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population.

Adoptive Cell Transfer

Ex vivo

10.4049/jimmunol.188.supp.179.19

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The Journal of Experimental Medicine (2021)

Vanessa Sancho‐Shimizu Petter Brodin Aurélie Cobat Catherine M. Biggs Julie Toubiana

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

Pathogenesis

Viral Pathogenesis

Viral infection

10.1084/jem.20210446

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Citations (134)

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

JCI Insight (2022)

Erica G. Schmitt Kelsey A. Toth Samuel I. Risma Ana Kolicheski Nermina Saucier

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

Immune Dysregulation

Regulatory T cell

Pathogenesis

10.1172/jci.insight.162695

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Citations (19)

Interleukin 4 increases the production of induced regulatory T cells in C57BL/6 mice

Inflammatory Bowel Diseases (2011)

Dipica Haribhai Erica G. Schmitt Jennifer Ziegelbauer Kyle Upchurch Nita H. Salzman

Naïve peripheral T cells can express the transcription factor Foxp3 and develop regulatory function. These “induced” regulatory T (iTreg) cells are essential for tolerance and complement the function of other regulatory populations. In this study we used the lymphopenia-associated model of colitis to compare the kinetics of iTreg cell production in both C57BL/6 and BALB/c mice, the prototypical Th1- and Th2-type strains. Following the adoptive transfer of naïve CD4+ T cells into Rag−/− recipients, we tracked the development of iTreg cells over a period of 40 days. Whereas iTreg cell production in C57BL/6 was minimal, by 10 days there was a relative five-fold increase in the number of iTreg cells in BALB/c mice that grew to 35 fold by 40 days. This dramatic increase in iTreg cells correlated with a similar increase in IL-17A producing cells in the mesenteric lymph nodes and gut of BALB/c mice. In contrast, the proportion of CD4+ T cells that produced IFN-γ was comparable between the two strains. Pretreatment of C57BL/6 Rag−/− recipient mice with IL-4 resulted in a six-fold increase in the number of iTreg cells compared to untreated mice. These results indicate that a Th2 milieu supports iTreg cell induction.

Adoptive Cell Transfer

Mesenteric lymph nodes

10.1097/00054725-201112002-00275

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Induced regulatory T cell-derived interleukin 10 is required for the cure of experimental colitis

Inflammatory Bowel Diseases (2011)

Erica G. Schmitt Dipica Haribhai Jason B. Williams Praful Aggarwal Ulrich Broeckel

Induced Treg (iTreg) cells are essential for tolerance. Although in vitro derived iTreg cells can be used therapeutically in preclinical models of autoimmune disease, their stability in vivo and their mechanisms of suppression have not been examined. Here, we used a treatment model of lymphopenia-associated colitis to examine the role of IL-10 in iTreg cell function. Monotherapy with IL-10 sufficient but not IL-10 deficient iTreg cells slowed the onset of colitis and decreased colon infiltration, but did not resolve disease. Mice treated with both nTreg and iTreg cells survived and gained weight when IL-10 was present in at least one Treg compartment, even though the iTreg cells comprised at most ∽20% of all Treg cells in the treated mice. Importantly, ∽75% of these in vitro derived iTreg cells lost Foxp3 expression and remained in the MLN as ex-iTreg cells that now expressed the proinflammatory cytokines IFN-γ or IL-17A. The TCR repertoires of iTreg and exiTreg cells shared minimal overlap, indicating independent peripheral selection of the iTreg and ex-iTreg compartments based on antigen specificity. These data demonstrate a potent, additive effect of IL-10 produced by iTreg cells in the treatment of colitis that effectively compensates for the inherent instability of in vitro derived iTreg cells and their propensity to develop pathogenic effector function.

Adoptive Cell Transfer

Proinflammatory cytokine

Ex vivo

10.1097/00054725-201112002-00025

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Amplified STAT3 increases expression of the CD39 ectoenzyme and impairs function of CD8+ T cells.

The Journal of Immunology (2024)

José Durán Samir Sayed Montana Knight Megan C. Dalalo Peyton E. Conrey

Abstract Regulation of T cell signaling is paramount to mount an appropriate immune response and protect the host from pathophysiology. Here, we study the impact on CD8+ T cells in monogenic inborn error of immunity patients exhibiting dysregulated signal 3 (cytokine signaling) pathways resulting from STAT3 gain- or loss-of-function variants (STAT3 GOF and STAT3 LOF). Using high dimensional immune profiling, we demonstrate increased expression of the ectoenzyme, CD39, which hydrolyzes extracellular ATP, on STAT3 GOF patient CD8+ T cells. Moreover, CD8+ T cells from two mouse models of STAT3 GOF (STAT3+/G421R and NOD-STAT3+/K392R) recapitulated this increase in CD39. In vitro, STAT3-activating cytokines (e.g., IL-6, IL-21, IL-27, IL-10) augment CD39 induction in a TCR-dependent manner in healthy donor and in STAT3 GOF CD8+ T cells. In contrast, STAT3 LOF patients show diminished CD39 induction. We find a positive correlation between CD39 induction and phosphorylated STAT3 levels while STAT3 inhibition prevents this cytokine-driven augmentation of CD39. Finally, acutely activated, and sorted CD39+CD8+ T cells from healthy donors inhibit bystander CD8+ T cell cytokine production (e.g., IFN-g). Pharmacologic inhibition of CD39 enzymatic activity or genetic ablation via CRISPR/Cas9 editing reversed decreases in cytokine production. Together, our data demonstrate a mechanistic connection between amplified STAT3 signaling and CD39 levels which is capable of impairing CD8+ T cell function.

Expression (computer science)

10.4049/jimmunol.212.supp.0800.6275

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