A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

Simone Caielli; Diogo Troggian Veiga; Preetha Balasubramanian; Shruti Athale; Bojana Domic; Elise Murat; Romain Banchereau; Zhaohui Xu; Manjari Chandra; Cheng Han Chung; Lynnette Walters; Jeanine Baisch; Tracey Wright; Marilynn Punaro; Lorien A Nassi; Katie Stewart; Julie Fuller; Duygu Ucar; Hideki Ueno; Joseph Zhou; Jacques Banchereau; Virginia Pascual

doi:10.1038/s41591-018-0254-9

A CD4⁺ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

Simone Caielli, Diogo Troggian Veiga, Preetha Balasubramanian, Shruti Athale, Bojana Domic, Elise Murat, Romain Banchereau, Zhaohui Xu, Manjari Chandra, Cheng Han Chung, Lynnette Walters, Jeanine Baisch, Tracey Wright, Marilynn Punaro, Lorien A Nassi, Katie Stewart, Julie Fuller, Duygu Ucar, Hideki Ueno, Joseph ZhouJacques Banchereau, Virginia Pascual

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

167 Scopus citations

Abstract

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)¹. Follicular helper T cells (T_FH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers². Here, we describe a CXCR5⁻CXCR3⁺ programmed death 1 (PD1)^hiCD4⁺ helper T cell population distinct from T_FH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4⁺ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand³. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

Original language	English (US)
Pages (from-to)	75-81
Number of pages	7
Journal	Nature medicine
Volume	25
Issue number	1
DOIs	https://doi.org/10.1038/s41591-018-0254-9
State	Published - Jan 1 2019

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41591-018-0254-9

Cite this

Caielli, S., Veiga, D. T., Balasubramanian, P., Athale, S., Domic, B., Murat, E., Banchereau, R., Xu, Z., Chandra, M., Chung, C. H., Walters, L., Baisch, J., Wright, T., Punaro, M., Nassi, L. A., Stewart, K., Fuller, J., Ucar, D., Ueno, H., ... Pascual, V. (2019). A CD4⁺ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nature medicine, 25(1), 75-81. https://doi.org/10.1038/s41591-018-0254-9

Caielli, S, Veiga, DT, Balasubramanian, P, Athale, S, Domic, B, Murat, E, Banchereau, R, Xu, Z, Chandra, M, Chung, CH, Walters, L, Baisch, J, Wright, T, Punaro, M, Nassi, LA, Stewart, K, Fuller, J, Ucar, D, Ueno, H, Zhou, J, Banchereau, J & Pascual, V 2019, 'A CD4⁺ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate', Nature medicine, vol. 25, no. 1, pp. 75-81. https://doi.org/10.1038/s41591-018-0254-9

@article{5ceab4fb26b44afdbc3daca5b84640cd,

title = "A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate",

abstract = "Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5−CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.",

author = "Simone Caielli and Veiga, {Diogo Troggian} and Preetha Balasubramanian and Shruti Athale and Bojana Domic and Elise Murat and Romain Banchereau and Zhaohui Xu and Manjari Chandra and Chung, {Cheng Han} and Lynnette Walters and Jeanine Baisch and Tracey Wright and Marilynn Punaro and Nassi, {Lorien A} and Katie Stewart and Julie Fuller and Duygu Ucar and Hideki Ueno and Joseph Zhou and Jacques Banchereau and Virginia Pascual",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

day = "1",

doi = "10.1038/s41591-018-0254-9",

language = "English (US)",

volume = "25",

pages = "75--81",

journal = "Nature medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

AU - Caielli, Simone

AU - Veiga, Diogo Troggian

AU - Balasubramanian, Preetha

AU - Athale, Shruti

AU - Domic, Bojana

AU - Murat, Elise

AU - Banchereau, Romain

AU - Xu, Zhaohui

AU - Chandra, Manjari

AU - Chung, Cheng Han

AU - Walters, Lynnette

AU - Baisch, Jeanine

AU - Wright, Tracey

AU - Punaro, Marilynn

AU - Nassi, Lorien A

AU - Stewart, Katie

AU - Fuller, Julie

AU - Ucar, Duygu

AU - Ueno, Hideki

AU - Zhou, Joseph

AU - Banchereau, Jacques

AU - Pascual, Virginia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5−CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

AB - Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5−CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

UR - http://www.scopus.com/inward/record.url?scp=85057454532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057454532&partnerID=8YFLogxK

U2 - 10.1038/s41591-018-0254-9

DO - 10.1038/s41591-018-0254-9

M3 - Article

C2 - 30478422

AN - SCOPUS:85057454532

SN - 1078-8956

VL - 25

SP - 75

EP - 81

JO - Nature medicine

JF - Nature medicine

IS - 1

ER -

A CD4⁺ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this