Notch2-dependent DC2s mediate splenic germinal center responses

Carlos G. Briseño; Ansuman T. Satpathy; Jesse T. Davidson; Stephen T. Ferris; Vivek Durai; Prachi Bagadia; Kevin W. O'Connor; Derek J. Theisen; Theresa L. Murphy; Kenneth M. Murphy

doi:10.1073/pnas.1809925115

Notch2-dependent DC2s mediate splenic germinal center responses

Carlos G. Briseño, Ansuman T. Satpathy, Jesse T. Davidson, Stephen T. Ferris, Vivek Durai, Prachi Bagadia, Kevin W. O'Connor, Derek J. Theisen, Theresa L. Murphy, Kenneth M. Murphy

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

42 Scopus citations

Abstract

CD4⁺ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation ofMHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.

Original language	English
Pages (from-to)	10726-10731
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	42
DOIs	https://doi.org/10.1073/pnas.1809925115
State	Published - Oct 16 2018

Keywords

Dendritic cell
Germinal center
T follicular helper cell

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10.1073/pnas.1809925115

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@article{0fee2b7a10a5436d8bef15d462182d81,

title = "Notch2-dependent DC2s mediate splenic germinal center responses",

abstract = "CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation ofMHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.",

keywords = "Dendritic cell, Germinal center, T follicular helper cell",

author = "Brise{\~n}o, {Carlos G.} and Satpathy, {Ansuman T.} and Davidson, {Jesse T.} and Ferris, {Stephen T.} and Vivek Durai and Prachi Bagadia and O'Connor, {Kevin W.} and Theisen, {Derek J.} and Murphy, {Theresa L.} and Murphy, {Kenneth M.}",

note = "Funding Information: St. Louis for help with genomic analysis. The Center is supported by Cancer Center Support Grant P30 CA91842 from the National Cancer Institute and by Institute of Clinical and Translational Sciences/Clinical and Translational Science Award UL1 TR000448 from the National Center for Research Resources. A.T.S. is supported by a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy. V.D. and D.J.T. are supported by the National Institutes of Health (Grants F30DK108498 and T32 AI007163-40, respectively). J.T.D. is supported by the National Cancer Institute (Grant T32 CA 009621), and P.B. is supported by the National Science Foundation (Grant DGE-1143954). K.M.M. is supported by the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",

year = "2018",

month = oct,

day = "16",

doi = "10.1073/pnas.1809925115",

language = "English",

volume = "115",

pages = "10726--10731",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - Notch2-dependent DC2s mediate splenic germinal center responses

AU - Briseño, Carlos G.

AU - Satpathy, Ansuman T.

AU - Davidson, Jesse T.

AU - Ferris, Stephen T.

AU - Durai, Vivek

AU - Bagadia, Prachi

AU - O'Connor, Kevin W.

AU - Theisen, Derek J.

AU - Murphy, Theresa L.

AU - Murphy, Kenneth M.

N1 - Funding Information: St. Louis for help with genomic analysis. The Center is supported by Cancer Center Support Grant P30 CA91842 from the National Cancer Institute and by Institute of Clinical and Translational Sciences/Clinical and Translational Science Award UL1 TR000448 from the National Center for Research Resources. A.T.S. is supported by a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy. V.D. and D.J.T. are supported by the National Institutes of Health (Grants F30DK108498 and T32 AI007163-40, respectively). J.T.D. is supported by the National Cancer Institute (Grant T32 CA 009621), and P.B. is supported by the National Science Foundation (Grant DGE-1143954). K.M.M. is supported by the Howard Hughes Medical Institute. Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.

PY - 2018/10/16

Y1 - 2018/10/16

N2 - CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation ofMHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.

AB - CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation ofMHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.

KW - Dendritic cell

KW - Germinal center

KW - T follicular helper cell

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U2 - 10.1073/pnas.1809925115

DO - 10.1073/pnas.1809925115

M3 - Article

C2 - 30279176

AN - SCOPUS:85055003131

SN - 0027-8424

VL - 115

SP - 10726

EP - 10731

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 42

ER -

Notch2-dependent DC2s mediate splenic germinal center responses

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