Identification of Novel CD4+ T Cell Subsets in the Target Tissue of Sjögren's Syndrome and Their Differential Regulation by the Lymphotoxin/LIGHT Signaling Axis.
Despite being one of the most common rheumatologic diseases, there is still no disease-modifying drug for primary Sjögren's syndrome (pSS). Advancing our knowledge of the target tissue has been limited by the low dimensionality of histology techniques and the small size of human salivary gland biopsies. In this study, we took advantage of a molecularly validated mouse model of pSS to characterize tissue-infiltrating CD4+T cells and their regulation by the lymphotoxin/LIGHT signaling axis. Novel cell subsets were identified by combining highly dimensional flow and mass cytometry with transcriptomic analyses. Pharmacologic modulation of the LTβR signaling pathway was achieved by treating mice with LTβR-Ig, a therapeutic intervention currently being tested in pSS patients (Baminercept trial NCT01552681). Using these approaches, we identified two novel CD4+T cell subsets characterized by high levels of PD1: Prdm1+effector regulatory T cells expressing immunoregulatory factors, such as Il10, Areg, Fgl2, and Itgb8, and Il21+effector conventional T cells expressing a pathogenic transcriptional signature. Mirroring these observations in mice, large numbers of CD4+PD1+T cells were detected in salivary glands from Sjögren's patients but not in normal salivary glands or kidney biopsies from lupus nephritis patients. Unexpectedly, LTβR-Ig selectively halted the recruitment of PD1-naive, but not PD1+, effector T cells to the target tissue, leaving the cells with pathogenic potential unaffected. Altogether, this study revealed new cellular players in pSS pathogenesis, their transcriptional signatures, and differential dependency on the lymphotoxin/LIGHT signaling axis that help to interpret the negative results of the Baminercept trial and will guide future therapeutic interventions.
Immunology Research, Biogen, Cambridge, MA 02142.
Scott
0000-0001-9853-5289
S
Haskett
Immunology Research, Biogen, Cambridge, MA 02142.
Jian
J
Ding
Immunology Research, Biogen, Cambridge, MA 02142.
Wei
W
Zhang
Immunology Research, Biogen, Cambridge, MA 02142.
Alice
A
Thai
Immunology Research, Biogen, Cambridge, MA 02142.
Patrick
P
Cullen
Immunology Research, Biogen, Cambridge, MA 02142.
Shanqin
S
Xu
Immunology Research, Biogen, Cambridge, MA 02142.
Britta
B
Petersen
Immunology Research, Biogen, Cambridge, MA 02142.
Galina
G
Kuznetsov
Immunology Research, Biogen, Cambridge, MA 02142.
Luke
0000-0002-5689-1784
L
Jandreski
Immunology Research, Biogen, Cambridge, MA 02142.
Stefan
S
Hamann
Immunology Research, Biogen, Cambridge, MA 02142.
Taylor L
0000-0002-6941-0900
TL
Reynolds
Immunology Research, Biogen, Cambridge, MA 02142.
Norm
N
Allaire
Immunology Research, Biogen, Cambridge, MA 02142.
Timothy S
TS
Zheng
Immunology Research, Biogen, Cambridge, MA 02142 michael.mingueneau@biogen.com.
Michael
M
Mingueneau
D066258:Amphiregulin / Q000235:genetics; D000818:Animals; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D007668:Kidney / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012469:Salivary Glands / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000503:physiopathology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*; D000098546:Interleukin-21
D066258:Amphiregulin; C587849:Areg protein, mouse; C556062:IL10 protein, mouse; D007378:Interleukins; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D016753:Interleukin-10; D000098546:Interleukin-21