Identification of a T follicular helper cell subset that drives anaphylactic IgE

Uthaman Gowthaman; Jennifer S. Chen; Biyan Zhang; William F. Flynn; Yisi Lu; Wenzhi Song; Julie Joseph; Jake A. Gertie; Lan Xu; Magalie A. Collet; Jessica D.S. Grassmann; Tregony Simoneau; David Chiang; M. Cecilia Berin; Joseph E. Craft; Jason S. Weinstein; Adam Williams; Stephanie C. Eisenbarth

doi:10.1126/science.aaw6433

Identification of a T follicular helper cell subset that drives anaphylactic IgE

Uthaman Gowthaman, Jennifer S. Chen, Biyan Zhang, William F. Flynn, Yisi Lu, Wenzhi Song, Julie Joseph, Jake A. Gertie, Lan Xu, Magalie A. Collet, Jessica D.S. Grassmann, Tregony Simoneau, David Chiang, M. Cecilia Berin, Joseph E. Craft, Jason S. Weinstein, Adam Williams^*, Stephanie C. Eisenbarth

^*Corresponding author for this work

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

336 Scopus citations

Abstract

Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (T_FH) cells direct the affinity and isotype of antibodies produced by B cells. Although T_FH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing T_FH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “T_FH13” cells have an unusual cytokine profile (IL-13^hiIL-4^hiIL-5^hiIL-21^lo) and coexpress the transcription factors BCL6 and GATA3. T_FH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T_FH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

Original language	English (US)
Article number	eaaw6433
Journal	Science
Volume	365
Issue number	6456
DOIs	https://doi.org/10.1126/science.aaw6433
State	Published - Aug 30 2019

Funding

We thank M. Firla for technical assistance; M. Wimsatt for the illustration; E. Gelfand (National Jewish Health, CO) for the Il13−/− bone marrow; C. Allen (UCSF) for IgE GC B cell staining protocol; R. D. Chow (Yale University) for discussions on analysis of scRNA-seq data; and the Single Cell Biology Laboratory led by P. Robson at the Jackson Laboratory for Genomic Medicine, for help with scRNA-seq experiments. Funding: This work was supported by Food Allergy Research and Education Ira and Diana Riklis Family Research Award in Food Allergy, R01 AI136942, and R01 AI108829 (to S.C.E.), and by R21 AI135221 and R21 AI133440 (to A.W.). U.G. is a recipient of Gershon-Trudeau Fellowship from Immunobiology at Yale University. B.Z. is a recipient of Ph.D. fellowship awarded by Agency for Science, Technology, and Research, Singapore. T.S. is a recipient of Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

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Gowthaman, U., Chen, J. S., Zhang, B., Flynn, W. F., Lu, Y., Song, W., Joseph, J., Gertie, J. A., Xu, L., Collet, M. A., Grassmann, J. D. S., Simoneau, T., Chiang, D., Cecilia Berin, M., Craft, J. E., Weinstein, J. S., Williams, A., & Eisenbarth, S. C. (2019). Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science, 365(6456), Article eaaw6433. https://doi.org/10.1126/science.aaw6433

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title = "Identification of a T follicular helper cell subset that drives anaphylactic IgE",

abstract = "Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “TFH13” cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.",

author = "Uthaman Gowthaman and Chen, {Jennifer S.} and Biyan Zhang and Flynn, {William F.} and Yisi Lu and Wenzhi Song and Julie Joseph and Gertie, {Jake A.} and Lan Xu and Collet, {Magalie A.} and Grassmann, {Jessica D.S.} and Tregony Simoneau and David Chiang and {Cecilia Berin}, M. and Craft, {Joseph E.} and Weinstein, {Jason S.} and Adam Williams and Eisenbarth, {Stephanie C.}",

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doi = "10.1126/science.aaw6433",

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Gowthaman, U, Chen, JS, Zhang, B, Flynn, WF, Lu, Y, Song, W, Joseph, J, Gertie, JA, Xu, L, Collet, MA, Grassmann, JDS, Simoneau, T, Chiang, D, Cecilia Berin, M, Craft, JE, Weinstein, JS, Williams, A & Eisenbarth, SC 2019, 'Identification of a T follicular helper cell subset that drives anaphylactic IgE', Science, vol. 365, no. 6456, eaaw6433. https://doi.org/10.1126/science.aaw6433

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AU - Gowthaman, Uthaman

AU - Chen, Jennifer S.

AU - Zhang, Biyan

AU - Flynn, William F.

AU - Lu, Yisi

AU - Song, Wenzhi

AU - Joseph, Julie

AU - Gertie, Jake A.

AU - Xu, Lan

AU - Collet, Magalie A.

AU - Grassmann, Jessica D.S.

AU - Simoneau, Tregony

AU - Chiang, David

AU - Cecilia Berin, M.

AU - Craft, Joseph E.

AU - Weinstein, Jason S.

AU - Williams, Adam

AU - Eisenbarth, Stephanie C.

PY - 2019/8/30

Y1 - 2019/8/30

N2 - Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “TFH13” cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

AB - Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “TFH13” cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

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Identification of a T follicular helper cell subset that drives anaphylactic IgE

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