Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells
Brinda Monian, Ang A Tu, Bert Ruiter, Duncan M Morgan, Patrick M Petrossian, Neal P Smith, Todd M Gierahn, Julia H Ginder, Wayne G Shreffler, J Christopher Love, Brinda Monian, Ang A Tu, Bert Ruiter, Duncan M Morgan, Patrick M Petrossian, Neal P Smith, Todd M Gierahn, Julia H Ginder, Wayne G Shreffler, J Christopher Love
Abstract
Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper-like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.
Trial registration: ClinicalTrials.gov NCT01750879.
Keywords: Allergy; Immunology; T cells.
Figures
References
- Patil SU, et al. Peanut oral immunotherapy transiently expands circulating Ara h 2-specific B cells with a homologous repertoire in unrelated subjects. J Allergy Clin Immunol. 2015;136(1):125–134. doi: 10.1016/j.jaci.2015.03.026.
- Sicherer SH, Sampson HA. Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018;141(1):41–58. doi: 10.1016/j.jaci.2017.11.003.
- Gupta RS, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9–17. doi: 10.1542/peds.2011-0204.
- Vickery BP, et al. Pathophysiology of food allergy. Pediatr Clin North Am. 2011;58(2):363–376. doi: 10.1016/j.pcl.2011.02.012.
- Prussin C, et al. TH2 heterogeneity: does function follow form? J Allergy Clin Immunol. 2010;126(6):1094–1098. doi: 10.1016/j.jaci.2010.08.031.
- Sampath V, Nadeau KC. Newly identified T cell subsets in mechanistic studies of food immunotherapy. J Clin Invest. 2019;129(4):1431–1440. doi: 10.1172/JCI124605.
- Wambre E, et al. A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci Transl Med. 2017;9(401):eaam9171. doi: 10.1126/scitranslmed.aam9171.
- Gowthaman U, et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science. 2019;365(6456):eaaw6433. doi: 10.1126/science.aaw6433.
- Mitson-Salazar A, et al. Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. J Allergy Clin Immunol. 2016;137(3):907–918. doi: 10.1016/j.jaci.2015.08.007.
- Ruiter B, et al. Expansion of the CD4+ effector T-cell repertoire characterizes peanut-allergic patients with heightened clinical sensitivity. J Allergy Clin Immunol. 2020;145(1):270–282. doi: 10.1016/j.jaci.2019.09.033.
- Vickery BP, et al. AR101 oral immunotherapy for peanut allergy. N Engl J Med. 2018;379(21):1991–2001. doi: 10.1056/NEJMoa1812856.
- Chinthrajah RS, et al. Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2019;394(10207):1437–1449. doi: 10.1016/S0140-6736(19)31793-3.
- Blumchen K, et al. Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol. 2010;126(1):83–91. doi: 10.1016/j.jaci.2010.04.030.
- Vickery BP, et al. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol. 2014;133(2):468–475. doi: 10.1016/j.jaci.2013.11.007.
- Blumchen K, et al. Efficacy, safety, and quality of life in a multicenter, randomized, placebo-controlled trial of low-dose peanut oral immunotherapy in children with peanut allergy. J Allergy Clin Immunol Pract. 2019;7(2):479–491. doi: 10.1016/j.jaip.2018.10.048.
- Kim EH, et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2011;127(3):640–646. doi: 10.1016/j.jaci.2010.12.1083.
- Ryan JF, et al. Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets. Proc Natl Acad Sci U S A. 2016;113(9):E1286–E1295. doi: 10.1073/pnas.1520180113.
- Frischmeyer-Guerrerio PA, et al. Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2017;140(4):1043–1053. doi: 10.1016/j.jaci.2017.03.028.
- Syed A, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3) J Allergy Clin Immunol. 2014;133(2):500–510. doi: 10.1016/j.jaci.2013.12.1037.
- Varshney P, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127(3):654–660. doi: 10.1016/j.jaci.2010.12.1111.
- Weissler KA, et al. Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut. J Allergy Clin Immunol. 2018;141(5):1699–1710. doi: 10.1016/j.jaci.2018.01.035.
- Wang W, et al. Transcriptional changes in peanut-specific CD4+ T cells over the course of oral immunotherapy. Clin Immunol. 2020;219(march):108568.
- Wambre E. Effect of allergen-specific immunotherapy on CD4+ T cells. Curr Opin Allergy Clin Immunol. 2015;15(6):581–587. doi: 10.1097/ACI.0000000000000216.
- Tordesillas L, Berin MC. Mechanisms of oral tolerance. Clin Rev Allergy Immunol. 2018;55(2):107–117. doi: 10.1007/s12016-018-8680-5.
- Chiang D, et al. Single-cell profiling of peanut-responsive T cells in patients with peanut allergy reveals heterogeneous effector TH2 subsets. J Allergy Clin Immunol. 2018;141(6):2107–2120. doi: 10.1016/j.jaci.2017.11.060.
- Jones SM, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009;124(2):292–300. doi: 10.1016/j.jaci.2009.05.022.
- Chattopadhyay PK, et al. A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles. Nat Med. 2005;11(10):1113–1117. doi: 10.1038/nm1293.
- Chattopadhyay PK, et al. Live-cell assay to detect antigen-specific CD4+ T-cell responses by CD154 expression. Nat Protoc. 2006;1(1):1–6. doi: 10.1038/nprot.2006.1.
- Bacher P, et al. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell. 2016;167(4):1067–1078. doi: 10.1016/j.cell.2016.09.050.
- Aguet F, et al. Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–213. doi: 10.1038/nature24277.
- Liu K, et al. Augmentation in expression of activation-induced genes differentiates memory from naive CD4+ T cells and is a molecular mechanism for enhanced cellular response of memory CD4+ T cells. J Immunol. 2001;166(12):7335–7344. doi: 10.4049/jimmunol.166.12.7335.
- Kunnath-Velayudhan S, et al. Transcriptome analysis of mycobacteria-specific CD4+ T cells identified by activation-induced expression of CD154. J Immunol. 2017;199(7):2596–2606. doi: 10.4049/jimmunol.1700654.
- Commandeur S, et al. Clonal analysis of the T-cell response to in vivo expressed mycobacterium tuberculosis protein Rv2034, using a CD154 expression based T-cell cloning method. PLoS One. 2014;9(6):e99203. doi: 10.1371/journal.pone.0099203.
- Huang H, et al. Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor clustering with GLIPH2 and genome-wide antigen screening. Nat Biotechnol. 2020;38(10):1149–1202.
- Smith NP, et al. Identification of antigen-specific TCR sequences based on biological and statistical enrichment in unselected individuals. JCI Insight. 2021;6(13):e140028. doi: 10.1172/jci.insight.140028.
- Gierahn TM, et al. Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods. 2017;14(4):395–398. doi: 10.1038/nmeth.4179.
- Tu AA, et al. TCR sequencing paired with massively parallel 3’ RNA-seq reveals clonotypic T cell signatures. Nat Immunol. 2019;20(12):1692–1699. doi: 10.1038/s41590-019-0544-5.
- Witten DM, et al. A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis. Biostatistics. 2009;10(3):515–534. doi: 10.1093/biostatistics/kxp008.
- Kim CJ, et al. The transcription factor Ets1 suppresses T follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus. Immunity. 2018;49(6):1034–1048. doi: 10.1016/j.immuni.2018.10.012.
- NovalRivas M, et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 2015;42(3):512–523. doi: 10.1016/j.immuni.2015.02.004.
- Velu V, et al. Induction of Th1-biased T follicular helper (Tfh) cells in lymphoid tissues during chronic simian immunodeficiency virus infection defines functionally distinct germinal center Tfh cells. J Immunol. 2016;197(5):1832–1842. doi: 10.4049/jimmunol.1600143.
- Morgan DM, et al. Clonally expanded, GPR15-expressing pathogenic effector TH2 cells are associated with eosinophilic esophagitis. Sci Immunol. 2021;6(62):eabi5586. doi: 10.1126/sciimmunol.abi5586.
- Sonoda E, et al. Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production. J Exp Med. 1989;170(4):1415–1420. doi: 10.1084/jem.170.4.1415.
- Coffman RL, et al. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989;170(3):1039–1044. doi: 10.1084/jem.170.3.1039.
- Seumois G, et al. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma. Sci Immunol. 2020;5(48):eaba6087. doi: 10.1126/sciimmunol.aba6087.
- James KR, et al. Distinct microbial and immune niches of the human colon. Nat Immunol. 2020;21(3):343–353. doi: 10.1038/s41590-020-0602-z.
- Dash P, et al. Quantifiable predictive features define epitope-specific T cell receptor repertoires. Nature. 2017;547(7661):89–93. doi: 10.1038/nature22383.
- Hayes SM, et al. TCR signal strength influences alphabeta/gammadelta lineage fate. Immunity. 2005;22(5):583–593. doi: 10.1016/j.immuni.2005.03.014.
- Daniels MA, Teixeiro E. TCR signaling in T cell memory. Front Immunol. 2015;6(dec):617.
- Snook JP, et al. TCR signal strength controls the differentiation of CD4+ effector and memory T cells. Sci Immunol. 2018;3(25):eaas9103. doi: 10.1126/sciimmunol.aas9103.
- Tubo NJ, et al. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell. 2013;153(4):785–796. doi: 10.1016/j.cell.2013.04.007.
- Kotov DI, et al. TCR affinity biases Th cell differentiation by regulating CD25, Eef1e1, and Gbp2. J Immunol. 2019;202(9):2535–2545. doi: 10.4049/jimmunol.1801609.
- Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol. 2017;17(9):535–544. doi: 10.1038/nri.2017.50.
- Choy DF, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7(301):301ra129.
- Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol. 2016;28(4):163–171. doi: 10.1093/intimm/dxw006.
- Luce S, et al. Th2A and Th17 cell frequencies and regulatory markers as follow-up biomarker candidates for successful multifood oral immunotherapy. Allergy. 2020;75(6):1513–1516. doi: 10.1111/all.14180.
- Guttman-Yassky E, et al. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144(2):482–493. doi: 10.1016/j.jaci.2018.11.053.
- Seshasayee D, et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J Clin Invest. 2007;117(12):3868–3878. doi: 10.1172/JCI33559.
- Habtezion A, et al. Leukocyte trafficking to the small intestine and colon. Gastroenterology. 2016;150(2):340–354. doi: 10.1053/j.gastro.2015.10.046.
- Adamczyk A, et al. Differential expression of GPR15 on T cells during ulcerative colitis. JCI Insight. 2017;2(8):e90585. doi: 10.1172/jci.insight.90585.
- Ovadia A, et al. Two different STAT1 gain-of-function mutations lead to diverse IFN-γ-mediated gene expression. NPJ Genom Med. 2018;3(1):23. doi: 10.1038/s41525-018-0063-6.
- Manohar M, et al. Immune changes beyond Th2 pathways during rapid multifood immunotherapy enabled with omalizumab. Allergy. 2021;76(9):2809–2826. doi: 10.1111/all.14833.
- U.S. Food & Drug Administration. Guidance for industry: pyrogen and endotoxins testing: questions and answers. Updated March 22, 2018. Accessed November 24, 2021.
- Macosko EZ, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161(5):1202–1214. doi: 10.1016/j.cell.2015.05.002.
- McInnes L, et al. UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction [preprint]. Posted on arXiv on September 18, 2020.
Source: PubMed