Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling

Circulating antibodies (Ab) are crucial mediators of protection against potentially pathogenic microbes, but Ab also can cause tissue damage or cellular dysfunction (Geyer et al., 2021; McGettigan and Debes, 2021; Olsen and Karp, 2014; Suurmond and Diamond, 2015; Tsokos et al., 2016). In both adaptive and pathological settings, Ab functions depend on their heavy chain class, affinity, and concentration (reviewed in Rajewsky, 1996; Lu et al., 2018; Alemán and Rosales, 2023). Increased affinity after initial and repeated immunizations can be selected in several ways, one of which involves processes that occur in the microanatomy of germinal centers (also known as secondary follicles; reviewed in Boothby et al., 2019; Elsner and Shlomchik, 2020; Victora and Nussenzweig, 2022). Progeny cells that survive a gauntlet of programmed death in selecting for continued clonal proliferation ultimately can generate either memory B cells (MBCs) or an end-stage descendant of the B lineage, the plasma cell (PC) (Victora and Nussenzweig, 2022; Good-Jacobson and Shlomchik, 2010; Adachi et al., 2015; Leach et al., 2019; Inoue and Kurosaki, 2024). The magnitude of PC output (the numbers generated after B cell activation) and their rates of immunoglobulin secretion (Inoue and Kurosaki, 2024; Ise and Kurosaki, 2019; Eyer et al., 2017; Eyer et al., 2020) determine the net output and steady-state concentrations of Ab. Accordingly, understanding mechanisms that regulate the qualities or quantities of Ab, and that reduce or enhance the efficiency of generating PC, are important goals.

To elicit protective Ab, immune exposures such as vaccination activate B cell proliferation, and some progeny of such activated B cells develop into Ab-secreting PC (Shapiro-Shelef and Calame, 2005; Robinson et al., 2020; Bhattacharya, 2022). Specificity is fostered by a reliance on signal initiation through the BCR, the clonal Ag receptor on mature B lymphocytes (Paus et al., 2006; Phan et al., 2006; Benson et al., 2007). The capacity to be activated, survival efficiency, rates of proliferation, and propensity to yield GC B cells or PC depend on an array of other signal-initiating receptors, among them CD19, co-stimulators such as CD40 (reviewed in Elgueta et al., 2009; Rathmell et al., 1996), the death receptor Fas (Rathmell et al., 1996), pattern recognition receptors in the TLR family (Eckl-Dorna and Batista, 2009; reviewed in Celhar et al., 2012; Fillatreau et al., 2021), and cytokine receptors (King and Mohrs, 2009; Pignarre et al., 2021; Duan et al., 2021; Ozaki et al., 2002; Ettinger et al., 2005). One consequence of activation is that B lymphoblasts dramatically increase expression of an array of nutrient transporters that include those for amino acids and for glucose (Caro-Maldonado et al., 2014; Cho et al., 2016; reviewed in Boothby et al., 2022). Beyond this general picture, however, the effects or outputs of receptors likely are scalar and conditional, that is dependent on other signals. For instance, antigen with a high affinity and high valency of the BCR epitope signals differently from a monovalent, lower-affinity antigen (Kurosaki, 1999; Marshall et al., 2000; Puffer et al., 2007; Mukherjee et al., 2013; Pone et al., 2022; Kato et al., 2020, reviewed in Kwak et al., 2019), and may influence generation of PC. Moreover, increased expression of TLR7 or type 1 interferon (IFN) receptor stimulation each reduces the capacity of B cells to maintain self-tolerance (Banchereau and Pascual, 2006; Green and Marshak-Rothstein, 2011; Hamilton et al., 2017; Domeier et al., 2018), presumably involving changes in the quantitative balance among signal transducers and transcription factors. At a later stage, the IL-21 receptor is crucial for PC differentiation (Ozaki et al., 2002). Moreover, IL-21 has recently been reported to promote affinity maturation of GC-derived PC (MacLean et al., 2025). Little is known about the relationships between signal strength and metabolism. In vitro experiments showed that hypoxia or genetically mediated stabilization of hypoxia-inducible transcription factors (HIFs) blunted activation-induced increases in amino acid uptake and transporter gene expression as well as GC and Ab responses (Cho et al., 2016; Li et al., 2021). However, it remains unclear if metabolism can modulate signaling.

Nonetheless, a substantial and increasing body of evidence indicates that nutrient supply, uptake, and intermediary metabolism influence the properties of adaptive immunity, in part by their effects on differentiation and function of cells that mediate host responses (reviewed in Pignarre et al., 2021; Edinger, 2007; Johnson et al., 2016; Ripperger and Bhattacharya, 2021). The bulk of evidence is from analyses of the differentiation and functions of T cells, macrophages, and dendritic cells and documents condition and cell type specificity of findings. Nonetheless, several analyses point to important effects on B cells as well. In addition to a function during B cell development, expression of the glucose transporter (GLUT)1 on mature B cells supported the initial GC size, the Ag-specific Ab responses derived from B cells, and affinity maturation (Caro-Maldonado et al., 2014; Brookens et al., 2024; Bierling et al., 2024).

Among nutrients, only the distribution and sufficiency of oxygen are readily measured, but such analyses consistently reveal evidence of functional hypoxia in follicles, most accentuated in GC (Cho et al., 2016; Li et al., 2021; Jellusova et al., 2017; Nakagawa et al., 2024). Consistent with and potentially as a result of the hypoxia, GC B cells can exhibit higher rates of glucose uptake with several-fold increased glucose oxidation as well as utilization in the pentose phosphate pathway (Cho et al., 2016; Brookens et al., 2024; Bierling et al., 2024; Jellusova et al., 2017). Moreover, the ability to feed intermediates into one-carbon metabolism via increased expression of the enzyme phosphoglycerate dehydrogenase was reported to be crucial for germinal center size and normal degrees of high-affinity antibody production (D’Avola et al., 2022). Cell-type- and stage-specific inactivation of Slc2a1, the gene that encodes GLUT1, indicates that the increased glucose uptake is crucial for both GC homeostasis and the capacity of B cells to yield antibody-secreting PC (Brookens et al., 2024; Bierling et al., 2024). Metabolomic analyses suggested that increases in anaplerotic conversion and usage of amino acids may be evoked in GLUT1-deficient B cells as a potential compensatory mechanism (Bierling et al., 2024). In parallel, however, a remarkable degree of metabolic flexibility was suggested by the in vitro finding that although glucose is essential for PC development and Ab production in the absence of other hexoses, mannose, and galactose together could substitute for glucose (Brookens et al., 2024). Thus, the reduced influx and availability of glucose reduced Ab responses and affinity maturation, but the decrease in these outputs fell short of what likely could be therapeutically meaningful. Moreover, the importance of feeding the increase in B cell-intrinsic generation of serine with diversion of 3-phosphoglycerate away from generating pyruvate raised the question whether the capacity of mitochondria to use this latter metabolite was important in promoting greater quality and quantity of Ab after immunization.

To explore these issues, we used both immunizations and in vitro analyses that leveraged genetic and pharmacological approaches to test the importance of glutaminolysis – on its own or in combination with a second pathway – in Ab responses. Glutamine concentrations in vitro were found to be crucial for class switching as well as PC and Ab production, and B cell type-restricted inactivation of the Gls gene, which encodes the glutaminase expressed in post-natal cells outside the liver, impaired the response to ovalbumin in one immunization model. Surprisingly, however, the anti-NP response in a hapten-carrier model was unaffected. However, a synergistic impact resulted when GLS depletion was combined with targeted loss of function for either GLUT1 (Slc2a1) or an essential subunit of a mitochondrial pyruvate import carrier (Mpc2) (Zangari et al., 2020; Lam et al., 2016). Thus, glutaminolysis promoted the anti-NP response only if glucose intake or pyruvate flux was impaired, revealing one limit imposed on the metabolic flexibility of B cells in their mediation of Ab responses. The combined restriction of two pathways that feed mitochondrial metabolism represented what can be termed ‘synthetic auxotrophy’ rather than synthetic lethality (Farmer et al., 2005; O’Neil et al., 2017), in that effects on differentiation were observed beyond the impacts on death or proliferation. Gene expression signatures in GC B cells highlighted a requirement for GLS in metabolic reprogramming, that is both amplification of glucose-stimulated proton secretion and a major increase in mitochondrial respiration between the first and second days after B cell activation. Surprisingly, MPC2 and GLS were found to promote not only IL-21-stimulated STAT3 activation but also an IFN response signature in addition to promoting increased respiration. Together, the results reveal that an interplay between two metabolic pathways unexpectedly converged on programming not only IL-21R activation of STAT3, PC differentiation, and high-affinity Ab responses, but also the tyrosyl and serine phosphorylation of STAT1 induced by type 1 and type 2 IFNs. These findings have important implications for diseases, such as systemic lupus erythematosus (SLE), in which B cells and their response to IFN are crucial elements of pathogenesis.

We and others have published examples of a metabolic flexibility in B lineage cells that appears to allow limit or negate the effects of loss-of-function mutations in key steps of intermediary metabolism (Brookens et al., 2024; Bierling et al., 2024; Li et al., 2024). These findings raise questions as to whether or not there are interventions that could more substantially interfere with the ongoing production of PCs secreting Ab or, conversely, which pathways might need to collaborate for promoting full-strength Ab responses. The work presented here supports three central insights. First, we have identified conditions under which the anti-NP response is relatively glutaminase-independent, both in the primary phase and upon recall stimulation of B cells. Despite this apparent independence, this enzyme central to processing of glutamine and to anaplerosis takes on a vital role if mitochondrial pyruvate import is impeded. A related point is that the findings underscore the fallacy in stating conclusions as if universally applicable, inasmuch as the effect of B cell specific loss-of-function for GLS depended on the nature of the immunization. Thus, the anti-ovalbumin response derived from GLS-depleted B cells was substantially reduced under one set of conditions where the anti-NP responses after multivalent hapten-carrier immunization with NP were not similarly reduced after isolated Gls gene inactivation. Mechanistically, the findings revealed that glutaminase activity promotes a progressive increase in mitochondrial respiration in a manner enhanced by pyruvate import, an alternative pathway for providing substrates to the TCA (Krebs) Cycle. A third major finding is that the efficiency of coupling IFN receptors to the tyrosyl and serine phosphorylation of STAT1 – and IL-21 stimulation to STAT3 – depends on the programming of intermediary metabolism in a manner linked to ROS homeostasis. Taken all together, the findings reveal not only new insights into how intermediary metabolism can modulate differentiation and receptor signaling, but suggest the potential for new interventions in autoimmune diseases driven by IFN effects and auto-Ab.

Although the impetus to this work is a basic question about the interplay of intermediary pathways of intracellular metabolism, a major practical implication of the findings presented here is translational. A self-reinforcing network of increased IFN production and pathological levels and persistence of auto-Ab production is characteristic of several autoimmune conditions of humans. SLE and rheumatoid arthritis (RA) are most common and studied, but this pairing also is involved in inflammatory myopathies and primary Sjogren’s syndrome (Rönnblom and Eloranta, 2013; Higgs et al., 2011). Effectiveness of therapeutic mAb for B cell depletion is best established in RA; unimpressive results in SLE raised concerns that disease might be perpetuated by long-lived PC that secrete auto-Ab, do not need BAFF, and are CD20^neg. However, dramatic results of testing CD19-directed chimeric Ag receptor T cells in patients with SLE and myositis showed that targeting B cells reduced clinical disease, IFN levels, and those of pathologic auto-Ab [(Müller et al., 2024), reviewed in Taubmann et al., 2024]. These effects imply that ongoing production of PC from B cells maintains IFN production and disease activity. Cost, production complexity, and risk profile mean that a need to identify other approaches that restrict the ongoing differentiation of B cells into PC remains, despite the dramatic results in patients with severe disease. The capacity of CB839 to collaborate with UK5099 to suppress both PC differentiation and responsiveness to IFNs suggests that this agent and glutaminase-specific inhibition in general merit further analysis. Since CB839 appeared safe in patients during phase 2 clinical testing (Lee et al., 2022), our finding of an interplay between the standard-of-care agent HCQ and CB839 in the inhibition of PC development in vitro similarly militates in favor of translational investigation. Which B cells are major sources of the PC that secrete pathological auto-Ab, and the extent to which SLE susceptibility might involve a distinct relationship between intermediary metabolism and PC differentiation, are important issues beyond the scope of the present study. Although the atypical MBC that are implicated in SLE pathogenesis (Dörner and Lipsky, 2024) were not specifically tested and one cannot exclude some contribution of Ag being presented to the remnant GC that persisted after primary immune challenge, our data suggest that inhibition of the pathways impacted MBCs that rapidly differentiated after a secondary challenge.

Another finding of the work bears both on consideration of the intersection of B cell metabolism and function after immunization, and perhaps on the relationship of our findings to SLE. Our data show that although the Ag-specific Ab response elicited by a protein, ovalbumin, was reduced by B cell-specific depletion of GLS in an allergic lung inflammation model of immunization, the anti-NP response was normal. Our finding that the metabolic requirements for Ab responses differed according to Ag or type of immunization raises questions that merit being worked out in future research. A key point is that immunization to elicit anti-NP responses usually is carried out with heavily haptenated carriers, that is many NP-groups on each protein molecule. In sharp contrast, a particular epitope in the carrier protein (ovalbumin, KLH, gamma globulin) will be monovalent unless part of an aggregate. Valency and the extent of BCR cross-linking influence signaling by the BCR, which in turn can affect metabolic regulators such as mTORC1 and c-Myc. A related possibility derives from the characteristics of the anti-NP response, which is dominated by a limited Ig heavy chain repertoire (Cumano and Rajewsky, 1985). Thus, intrinsic biochemical characteristics of V_H125:V_Lλ BCR interactions with NP might lead to programming metabolic requirements that differ from what is elicited by the BCR repertoire responding to ovalbumin. The issue of valency has a bearing on the pathological Ab in auto-immunity in that so many auto-Ab of SLE are directed against multivalent Ag such as dsDNA and ribonucleoprotein complexes (Olsen and Karp, 2014; Suurmond and Diamond, 2015; Tsokos et al., 2016; Caielli et al., 2023). Finally, the specific immunization regimen might affect the results. General issues of valency in engagement of BCR at the cell surface remain incompletely clarified despite years of papers, so extensive further studies will be needed to understand better the relationship to a specific step in intermediary metabolism. Nonetheless, a striking finding herein is that a vital requirement for glutaminolysis is cryptic in the anti-NP response until uncovered by reduced import rates of either glucose into cells or pyruvate into mitochondria.

Our findings directly connect to questions of metabolic flexibility, which is a central issue for the potential translatability or implications of intermediary metabolism in targeting immune responses or auto-immunity. Targeting a particular process is less likely to be efficacious to the extent that GC B cells, or B cells in general, can use alternatives and achieve normal responses or outputs. For instance, although there is evidence that the majority of energy generation by activated and GC B cells involves FA oxidation, most of it in mitochondria (Weisel et al., 2020; Li et al., 2024), elimination of a key step in mitochondrial acquisition and use of FAs had no impact on Ab responses or discernible reduction in GC or affinity maturation (Li et al., 2024). Alternatively, restricting cell-intrinsic generation of serine from a glycolytic intermediate represents one potential point of vulnerability that was not compensated by flexibility (D’Avola et al., 2022). Depletion of a major glucose transporter – and inferentially of reduced supply of glucose for some combination of NADPH regeneration from NADP, serine biosynthesis, oxidation, and perhaps other uses of glucose – also reduced GC size, Ab responses, and affinity maturation (Brookens et al., 2024; Bierling et al., 2024). However, the effect magnitude (reduction to ~1/4 normal) appeared less promising from the standpoint of potential treatment of autoimmunity. Metabolomic data suggested that increased anaplerosis was a compensatory mechanism that might have limited the severity of the defect in ASC generation and Ab responses of GLUT1-depleted B cells (Bierling et al., 2024). Our findings support this inference in that the defects with Slc2a1^ΔΔ or Mpc2^ΔΔ B cells were each dramatically amplified by impedance of glutaminolysis. The size of the differences, the impact on the IgG2(a/)c isotype that is particularly important in SLE pathogenesis (reviewed in Bonanni et al., 2015), and the vital functions of STAT1 induction by IFN receptors in autoimmune models (Domeier et al., 2016; Domeier et al., 2018) indicate that this synthetic auxotrophy merits translational consideration. Inasmuch as cancer cells commonly have increased ROS levels at steady state (Akter et al., 2026).

The finding that metabolism regulates cytokine receptor coupling to Jak-STAT pathways raised a subsidiary question. Might there be conditions in health or disease, independent from genetic or pharmaceutical loss of function, where reduced rates of αKG production co-exist with decreased glucose import or pyruvate import into mitochondria? Some tumor masses had low interstitial glucose (Ho et al., 2015; Chang et al., 2015), and insufficient dietary protein intake causes a substantial reduction in circulating glutamine (Nohr et al., 1986; Andrews and Griffiths, 2002; Taylor et al., 2013; Raybuck and Boothby, unpublished data). Thus, decreased glutamine and glucose utilization may co-exist during short-term protein malnutrition after surgery of patients with residual tumor masses. A related circumstance could be for B cells in hypoxic regions of a tumor mass in cancer. Hypoxia tends to activate pyruvate dehydrogenase kinases, enzymes that decrease the generation of Ac-CoA from pyruvate, and indeed may also decrease mitochondrial pyruvate import (Golias et al., 2016; Ruiz-Iglesias and Mañes, 2021). Although hypoxia tends to increase glutamine uptake in cancer cell models, our prior work indicated that this stimulus and HIF stabilization in B cells decreased their uptake of a.a. such as glutamine. Moreover, decreased glutaminolysis by cancer cells (i.e. their glutamine use) increased micro-environmental glutamine and the functionality of tumor-infiltrating lymphocytes – indicating that glutamine was limiting in the TME (Edwards et al., 2021) – as has been reported for glucose (Ho et al., 2015; Chang et al., 2015). Since IFN-γ responsiveness is crucial in anti-tumor immunity and B cells tend to contribute to checking tumor growth (reviewed in Ikeda et al., 2002; Sarvaria et al., 2017; Laumont et al., 2022), the findings here have potential implications for one means by which cancer cell effects on nutrient micro-environments may assist in immune evasion.

RNA-seq data are publicly available through the Gene Expression Omnibus (GEO) resource of the US National Center for Bio-InformaticsBioinformatics (NCBI), using accession numbers GSE341991 (in vitro cultured B cells during differentiation to Ab-secreting cells) and GSE338789 (flow purified naive and GC B cells). Quantitative data in support of the graphical figure panels have been included as source data files.

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Author details

1. Sung Hoon Cho

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Present address

   Department of Medicine, Division of Rheumatology, Emory University School of Medicine, Atlanta, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Contributed equally with

   Shawna K Brookens, Ariel L Raybuck, Kaylor Meyer and Yeeun Paik

   For correspondence

   sung.hoon.cho@emory.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6463-4032

2. Shawna K Brookens

   1. Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States
   2. Cancer Biology Program, Vanderbilt University, Nashville, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – review and editing

   Contributed equally with

   Sung Hoon Cho, Ariel L Raybuck, Kaylor Meyer and Yeeun Paik

   Competing interests

   No competing interests declared

3. Ariel L Raybuck

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Project administration

   Contributed equally with

   Sung Hoon Cho, Shawna K Brookens, Kaylor Meyer and Yeeun Paik

   Competing interests

   No competing interests declared

4. Kaylor Meyer

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck and Yeeun Paik

   Competing interests

   No competing interests declared

5. Yeeun Paik

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Methodology

   Contributed equally with

   Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck and Kaylor Meyer

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0004-9369-2890

6. Jennie Hamilton

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

7. Jingxin Li

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

8. Karel Kalecky

   Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

9. Chloe Park

   Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

   Contribution

   Data curation, Software, Formal analysis, Investigation

   Competing interests

   No competing interests declared

10. Juyeon Lim

    Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

    Contribution

    Resources, Investigation, Methodology

    Competing interests

    No competing interests declared

11. Sakeenah L Hicks

    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, United States

    Contribution

    Data curation, Software, Validation, Methodology

    Competing interests

    No competing interests declared

12. John Karijolich

    Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States

    Contribution

    Software, Investigation, Project administration

    Competing interests

    No competing interests declared

13. Teodoro H Bottiglieri

    Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, United States

    Contribution

    Data curation, Formal analysis, Supervision, Investigation, Methodology, Project administration

    Competing interests

    No competing interests declared

14. Jeffrey C Rathmell

    1. Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States
    2. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, United States
    3. Vanderbilt Center for Infection, Inflammation, Immunology (VI4), Vanderbilt University Medical Center, Nashville, United States

    Contribution

    Conceptualization, Resources, Funding acquisition, Methodology

    Competing interests

    Was once involved with Citryx (see manuscript)

    "This ORCID iD identifies the author of this article:" 0000-0002-4106-3396

15. Denis Mogilenko

    1. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, United States
    2. Vanderbilt Center for Infection, Inflammation, Immunology (VI4), Vanderbilt University Medical Center, Nashville, United States
    3. Department of Medicine, Rheumatology and Immunology Division, Vanderbilt University Medical Center, Nashville, United States

    Contribution

    Conceptualization, Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5427-5243

16. Christopher D Scharer

    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, United States

    Contribution

    Conceptualization, Data curation, Software, Formal analysis, Supervision, Investigation

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7716-8504

17. Mark R Boothby

    1. Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States
    2. Cancer Biology Program, Vanderbilt University, Nashville, United States
    3. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, United States
    4. Vanderbilt Center for Infection, Inflammation, Immunology (VI4), Vanderbilt University Medical Center, Nashville, United States
    5. Department of Medicine, Rheumatology and Immunology Division, Vanderbilt University Medical Center, Nashville, United States

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Methodology, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    mark.boothby@vumc.org

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-2593-8276

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