B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis

B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (TH) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor–primed TH cells. ICOS/ICOSL axis–mediated glucose incorporation and utilization were crucial for inflammatory TH subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory TH subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory TH cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory TH subsets.

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Follicular lymphoma tumor–infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation

Blood ◽

10.1182/blood-2011-03-340646 ◽

2011 ◽

Vol 118 (13) ◽

pp. 3591-3602 ◽

Cited By ~ 21

Author(s):

Shannon P. Hilchey ◽

Alexander F. Rosenberg ◽

Ollivier Hyrien ◽

Shelley Secor-Socha ◽

Matthew R. Cochran ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Follicular Lymphoma ◽

Critical Role ◽

Cell Receptor ◽

Effector Memory ◽

T Helper ◽

Th Cells ◽

Lineage Differentiation ◽

Th Cell

Abstract The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4+ T-helper cells (TH) compared with reactive and normal lymph node (NLN) TH cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory TH cells. We further show differences in the distribution and anatomical localization of CXCR5+ TH populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as TH2 and TH17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of TH1 and polyfunctional TH cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although TH-cell differentiation in FL is skewed compared with NLNs, FL TH cells should have the same intrinsic ability to elicit antitumor effector responses as NLN TH cells when tumor suppressive mechanisms are attenuated.

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TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

10.1101/616441 ◽

2019 ◽

Author(s):

Xu Jiang ◽

Shi-yu Wang ◽

Chen Zhou ◽

Jing-hua Wu ◽

Yu-hao Jiao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Th17 Cells ◽

Cell Receptor ◽

T Cell Subsets ◽

Effector Memory ◽

Systemic Autoimmune Disease ◽

Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

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Increased numbers of CD5+ B cells and T cell receptor (TCR) γδ+ T cells are associated with younger age of onset in rheumatoid arthritis (RA)

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.1996.tb08287.x ◽

2007 ◽

Vol 103 (3) ◽

pp. 353-356 ◽

Cited By ~ 14

Author(s):

J. HASSAN ◽

G. YANNI ◽

V. HEGARTY ◽

C. FEIGHERY ◽

B. BRESNIHAN ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

B Cells ◽

T Cell Receptor ◽

Age Of Onset ◽

Γδ T Cells ◽

Cell Receptor ◽

Younger Age

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T cell receptor β repertoires as novel diagnostic markers for systemic lupus erythematosus and rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215442 ◽

2019 ◽

Vol 78 (8) ◽

pp. 1070-1078 ◽

Cited By ~ 15

Author(s):

Xiao Liu ◽

Wei Zhang ◽

Ming Zhao ◽

Longfei Fu ◽

Limin Liu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

T Cell ◽

Autoimmune Diseases ◽

T Cell Receptor ◽

Lupus Erythematosus ◽

Cell Receptor ◽

Systemic Lupus ◽

Tcr Repertoire ◽

Tcr Diversity

ObjectiveT cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations.MethodsPeripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases.ResultsSignificant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases.ConclusionsThese characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.

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Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0708426104 ◽

2007 ◽

Vol 104 (43) ◽

pp. 17034-17039 ◽

Cited By ~ 196

Author(s):

H. G. Evans ◽

T. Suddason ◽

I. Jackson ◽

L. S. Taams ◽

G. M. Lord

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Toll Like Receptor ◽

T Helper ◽

T Helper 17 ◽

T Helper 17 Cells ◽

Activated Monocytes ◽

Receptor Ligation

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Distribution of T-cell receptor-bearing lymphocytes in the synovial membrane from patients with rheumatoid arthritis

Journal of Autoimmunity ◽

10.1016/s0896-8411(05)80040-x ◽

1990 ◽

Vol 3 (6) ◽

pp. 737-745 ◽

Cited By ~ 12

Author(s):

I CHAOUNI ◽

M RADAL ◽

J SIMONYLAFONTAINE ◽

B COMBE ◽

J SANY ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Receptor ◽

Synovial Membrane ◽

Cell Receptor

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Alteration of Interleukin 4 Production Results in the Inhibition of T Helper Type 2 Cell–Dominated Inflammatory Bowel Disease in T Cell Receptor α Chain–Deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.190.5.607 ◽

1999 ◽

Vol 190 (5) ◽

pp. 607-616 ◽

Cited By ~ 75

Author(s):

Hideki Iijima ◽

Ichiro Takahashi ◽

Daisuke Kishi ◽

Jin-Kyung Kim ◽

Sunao Kawano ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Bowel Disease ◽

Cell Receptor ◽

Interleukin 4 ◽

T Helper ◽

Inflammatory Bowel ◽

Α Chain

T cell receptor α chain–deficient (TCR-α−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α−/− mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.

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T cell-independent antibody-mediated clearance of polyoma virus in T cell-deficient mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.403 ◽

1996 ◽

Vol 183 (2) ◽

pp. 403-411 ◽

Cited By ~ 73

Author(s):

E Szomolanyi-Tsuda ◽

R M Welsh

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Nude Mice ◽

Knockout Mice ◽

Cell Receptor ◽

Genetically Engineered ◽

Scid Mice ◽

Myeloproliferative Disease ◽

Alpha Beta

Polyomavirus (PyV) infection of SCID mice, which lack functional T and B cells, leads to a lethal acute myeloproliferative disease (AMD) and to high levels of virus replication in several organs by two wk after infection. This is in contrast to infection of T cell-deficient athymic nude mice, which are resistant to acute PyV-induced disease and poorly replicate the virus in their organs. This major difference in the virus load and in the outcome of PyV infection between SCID and nude mice suggested that an efficient, T cell-independent antiviral mechanism operates in T cell-deficient, PyV infected mice. To investigate this possibility, mice with different genetically engineered T and/or B cell deficiencies and SCID mice adoptively reconstituted with B and/or T cells were infected with PyV. The results indicated that the presence of B cells in the absence of T cells protected mice from the AMD, and this was accompanied by a major reduction of PyV in all organs tested. Sera from PyV-infected T cell receptor (TCR) alpha beta knockout or TCR alpha beta gamma delta knockout mice contained IgG2a antibodies to PyV. Sera or purified immunoglobulin fractions from PyV-infected TCR alpha beta knockout mice protected SCID mice from the PyV-induced AMD. To our knowledge, this is the first report of an effective T cell-independent antibody response clearing a virus and changing the outcome of infection from 100% mortality to 100% survival.

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