Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

Calvin Law; Vanessa Sue Wacleche; Ye Cao; Arundhati Pillai; John Sowerby; Brandon Sowerby; Alice Horisberger; Sabrina Bracero; Viktoriya Skidanova; Zhihan J. Li; Ifeoluwakiisi  Adejoorin; Eilish Dillon; Isaac J. Benque; Diana Pena Nunez; Diamon P. Simmons; Joshua Keegan; Lin Chen; Tina Baker; Phillip Z. Brohawn; Hussein Al-Mossawi; Ling-Yang Hao; Brian Jones; Navin Rao; Yujie Qu; Stephen Alves; A. Helena Jonsson; Katharina S. Shaw; Ruth Ann Vleugels; Elena Massarotti; Karen H. Costenbader; Michael B. Brenner; James A. Lederer; Judd F. Hultquist; Jaehyuk Choi; Deepak A. Rao; Accelerating Medicines Partnership RA/SLE Network

doi:10.1038/s41586-024-07627-2

Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus

Calvin Law, Vanessa Sue Wacleche, Ye Cao, Arundhati Pillai, John Sowerby, Brandon Sowerby, Alice Horisberger, Sabrina Bracero, Viktoriya Skidanova, Zhihan J. Li, Ifeoluwakiisi Adejoorin, Eilish Dillon, Isaac J. Benque, Diana Pena Nunez, Diamon P. Simmons, Joshua Keegan, Lin Chen, Tina Baker, Phillip Z. Brohawn, Hussein Al-MossawiLing-Yang Hao, Brian Jones, Navin Rao, Yujie Qu, Stephen Alves, A. Helena Jonsson, Katharina S. Shaw, Ruth Ann Vleugels, Elena Massarotti, Karen H. Costenbader, Michael B. Brenner, James A. Lederer, Judd F. Hultquist, Jaehyuk Choi^*, Deepak A. Rao^*, Accelerating Medicines Partnership RA/SLE Network

^*Corresponding author for this work

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

Abstract

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions^1,2. Expansion of T follicular helper (T_FH) and T peripheral helper (T_PH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE^3,4. Human T_FH and T_PH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs.^5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13⁺ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4⁺ T cell phenotypes in patients with SLE, with expansion of PD-1⁺/ICOS⁺ CXCL13⁺ T cells and reduction of CD96^hi IL-22⁺ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4⁺ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13⁺ T_PH/T_FH cell differentiation and promote an IL-22⁺ phenotype. Type I interferon, a pathogenic driver of SLE⁷, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13⁺ T_PH/T_FH cells on a polarization axis opposite from T helper 22 (T_H22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

Original language	English
Pages (from-to)	857-866
Number of pages	33
Journal	Nature
Volume	631
DOIs	https://doi.org/10.1038/s41586-024-07627-2
Publication status	Published - 10 Jul 2024

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Publisher Correction: Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus
Law, C., Wacleche, V. S., Cao, Y., Pillai, A., Sowerby, J., Sowerby, B., Horisberger, A., Bracero, S., Skidanova, V., Li, Z. J., Adejoorin, I., Dillon, E., Benque, I. J., Pena Nunez, D., Simmons, D. P., Keegan, J., Chen, L., Baker, T., Brohawn, P. Z. & Al-Mossawi, H. & 16 others, Hao, L.-Y., Jones, B., Rao, N., Qu, Y., Alves, S., Jonsson, A. H., Shaw, K. S., Vleugels, R. A., Massarotti, E., Costenbader, K. H., Brenner, M. B., Lederer, J. A., Hultquist, J. F., Choi, J., Rao, D. A. & Accelerating Medicines Partnership RA/SLE Network, 26 Jul 2024, In: Nature. 631, 1 p.
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Cite this

Law, C., Wacleche, V. S., Cao, Y., Pillai, A., Sowerby, J., Sowerby, B., Horisberger, A., Bracero, S., Skidanova, V., Li, Z. J., Adejoorin, I., Dillon, E., Benque, I. J., Pena Nunez, D., Simmons, D. P., Keegan, J., Chen, L., Baker, T., Brohawn, P. Z., ... Accelerating Medicines Partnership RA/SLE Network (2024). Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus. Nature, 631, 857-866. https://doi.org/10.1038/s41586-024-07627-2

@article{0612e05b0d7f4df99ef2446428e2a7f3,

title = "Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus",

abstract = "Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.",

author = "Calvin Law and Wacleche, {Vanessa Sue} and Ye Cao and Arundhati Pillai and John Sowerby and Brandon Sowerby and Alice Horisberger and Sabrina Bracero and Viktoriya Skidanova and Li, {Zhihan J.} and Ifeoluwakiisi Adejoorin and Eilish Dillon and Benque, {Isaac J.} and {Pena Nunez}, Diana and Simmons, {Diamon P.} and Joshua Keegan and Lin Chen and Tina Baker and Brohawn, {Phillip Z.} and Hussein Al-Mossawi and Ling-Yang Hao and Brian Jones and Navin Rao and Yujie Qu and Stephen Alves and Jonsson, {A. Helena} and Shaw, {Katharina S.} and Vleugels, {Ruth Ann} and Elena Massarotti and Costenbader, {Karen H.} and Brenner, {Michael B.} and Lederer, {James A.} and Hultquist, {Judd F.} and Jaehyuk Choi and Rao, {Deepak A.} and {Accelerating Medicines Partnership RA/SLE Network} and Andrew Filer and Hayley Carr and Mark Maybury and Saba Nayar and Karim Raza and Ilfita Sahbudin and Dagmar Scheel-Toellner",

year = "2024",

month = jul,

day = "10",

doi = "10.1038/s41586-024-07627-2",

language = "English",

volume = "631",

pages = "857--866",

journal = "Nature",

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publisher = "Nature Publishing Group",

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Law, C, Wacleche, VS, Cao, Y, Pillai, A, Sowerby, J, Sowerby, B, Horisberger, A, Bracero, S, Skidanova, V, Li, ZJ, Adejoorin, I, Dillon, E, Benque, IJ, Pena Nunez, D, Simmons, DP, Keegan, J, Chen, L, Baker, T, Brohawn, PZ, Al-Mossawi, H, Hao, L-Y, Jones, B, Rao, N, Qu, Y, Alves, S, Jonsson, AH, Shaw, KS, Vleugels, RA, Massarotti, E, Costenbader, KH, Brenner, MB, Lederer, JA, Hultquist, JF, Choi, J, Rao, DA & Accelerating Medicines Partnership RA/SLE Network 2024, 'Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus', Nature, vol. 631, pp. 857-866. https://doi.org/10.1038/s41586-024-07627-2

TY - JOUR

T1 - Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

AU - Law, Calvin

AU - Wacleche, Vanessa Sue

AU - Cao, Ye

AU - Pillai, Arundhati

AU - Sowerby, John

AU - Sowerby, Brandon

AU - Horisberger, Alice

AU - Bracero, Sabrina

AU - Skidanova, Viktoriya

AU - Li, Zhihan J.

AU - Adejoorin, Ifeoluwakiisi

AU - Dillon, Eilish

AU - Benque, Isaac J.

AU - Pena Nunez, Diana

AU - Simmons, Diamon P.

AU - Keegan, Joshua

AU - Chen, Lin

AU - Baker, Tina

AU - Brohawn, Phillip Z.

AU - Al-Mossawi, Hussein

AU - Hao, Ling-Yang

AU - Jones, Brian

AU - Rao, Navin

AU - Qu, Yujie

AU - Alves, Stephen

AU - Jonsson, A. Helena

AU - Shaw, Katharina S.

AU - Vleugels, Ruth Ann

AU - Massarotti, Elena

AU - Costenbader, Karen H.

AU - Brenner, Michael B.

AU - Lederer, James A.

AU - Hultquist, Judd F.

AU - Choi, Jaehyuk

AU - Rao, Deepak A.

AU - Accelerating Medicines Partnership RA/SLE Network

AU - Filer, Andrew

AU - Carr, Hayley

AU - Maybury, Mark

AU - Nayar, Saba

AU - Raza, Karim

AU - Sahbudin, Ilfita

AU - Scheel-Toellner, Dagmar

PY - 2024/7/10

Y1 - 2024/7/10

N2 - Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

AB - Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

U2 - 10.1038/s41586-024-07627-2

DO - 10.1038/s41586-024-07627-2

M3 - Article

SN - 0028-0836

VL - 631

SP - 857

EP - 866

JO - Nature

JF - Nature

ER -

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

Abstract

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Publisher Correction: Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

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Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus

Publisher Correction: Interferon subverts an AHR–JUN axis to promote CXCL13⁺ T cells in lupus