Successful prevention and treatment of chronic colitis by elimination of highly interleukin-7 receptor expressing mucosal T cells

We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRα promoter developed chronic colitis in concert with the expression of SRα/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4–12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell–depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor γ/δ T cells and CD8α/α cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell–derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.

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IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00276.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. G745-G754 ◽

Cited By ~ 26

Author(s):

Eriko Okada ◽

Motomi Yamazaki ◽

Masanobu Tanabe ◽

Tsutomu Takeuchi ◽

Masanobu Nanno ◽

...

Keyword(s):

T Cells ◽

Cell Receptor ◽

Therapeutic Approaches ◽

Chronic Colitis ◽

Human Inflammatory Bowel Disease ◽

Inflammatory Bowel ◽

Mucosal T Cells ◽

In Vivo Administration

We have previously demonstrated that mucosal CD4+ T cells expressing high levels of IL-7 receptor (IL-7Rhigh) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7Rhigh memory CD4+ mucosal T cells and the exacerbation of colitis. We first showed that CD4+ lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-α-deficient (TCR-α−/−), and recombinase-activating gene (RAG)-2−/−-transferred mice with or without colitis showed phenotypes of memory cells, but only CD4+ LPLs from colitic mice showed IL-7Rhigh. In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4+, but not normal CD4+ LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7Rhigh memory CD4+ LPLs and thereby exacerbated chronic colitis in RAG-2−/− mice transferred with CD4+ LPLs from colitic TCR-α−/− mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-α−/− colitis with decreased expansion of CD4+ LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4+ T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease.

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Mucosal T Cells Expressing High Levels of IL-7 Receptor Are Potential Targets for Treatment of Chronic Colitis

The Journal of Immunology ◽

10.4049/jimmunol.171.3.1556 ◽

2003 ◽

Vol 171 (3) ◽

pp. 1556-1563 ◽

Cited By ~ 53

Author(s):

Motomi Yamazaki ◽

Tomoharu Yajima ◽

Masanobu Tanabe ◽

Kazuto Fukui ◽

Eriko Okada ◽

...

Keyword(s):

T Cells ◽

Chronic Colitis ◽

Mucosal T Cells

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Faculty Opinions recommendation of Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016385.200607 ◽

2003 ◽

Author(s):

Phillip Scott

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Memory Cells ◽

Interleukin 7 ◽

Selective Expression

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EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.368 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii89-ii89

Author(s):

Subhajit Ghosh ◽

Ran Yan ◽

Sukrutha Thotala ◽

Arijita Jash ◽

Anita Mahadevan ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cervical Lymph Nodes ◽

Cd8 Cells ◽

Interleukin 7 ◽

Long Acting ◽

Spleen And Lymph Nodes ◽

Mouse Glioma

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

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565 A novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0565 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A599-A599

Author(s):

Subhajit Ghosh ◽

Ran Yan ◽

Sukrutha Thotala ◽

Arijita Jash ◽

Anita Mahadevan ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Standard Of Care ◽

Control Group ◽

Cervical Lymph Nodes ◽

Cd8 Cells ◽

Interleukin 7 ◽

Long Acting

BackgroundRadiation (RT) and temozolomide (TMZ), which are standard of care for patients with glioblastoma (GBM), can cause prolonged severe lymphopenia. Lymphopenia, in turn, is an independent risk factor for shorter survival. Interleukin-7 (IL-7) is a cytokine that is required for T cell homeostasis and proliferation. IL-7 levels are inappropriately low in GBM patients with lymphopenia. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 rescues treatment-induced lymphopenia and improves survival.MethodsImmunocompetent C57BL/6 mice bearing two intracranial glioma models (GL261 and CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-I7 (10 mg/kg on the final day of RT completion). We profiled the CD3, CD8, CD4, FOXP3 cells in peripheral blood over time. We also immunoprofiled cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. Survival was monitored daily.ResultsMedian survival in mice treated with NT-I7 combined with RT was significantly longer than RT alone (GL261: 40d vs 34d, p<0.0021; CT2A: 90d vs 40d, p<0.0499) or NT-I7 alone (GL261: 40d vs 24d, p<0.008; CT2A: 90d vs 32d, p<0.0154). NT-I7 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261(40d vs 47d) and CT2A (90d vs 90d). Cytotoxic CD8+ T cells were increased in both peripheral blood (0.66 x 105 to 3.34 x 105; P≤0.0001) and tumor (0.53 x 103 to 1.83 x 103; P≤0.0001) in mice treated with NT-I7 when compared to control. Similarly, NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood (0.658 x 105 to 1.839 x 105 P≤0.0001) when compared to RT alone. There were decreases in tumor infiltrating FOXP3+ T-reg cells in mice treated with NT-I7 (1.9 x 104 to 0.75 x 104 P≤0.0001) and NT-I7 + RT (1.9 x 104 to 0.59 x 104 P≤0.0001) when compared to the control group without NT-I7. In addition, NT- I7 treatment increased CD8+ T cells in thymus, spleen, and lymph nodes.ConclusionsNT-I7 enhances cytotoxic CD8+ T lymphocytes systemically and in the tumor microenvironment, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

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Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽

10.1038/s41586-021-03752-4 ◽

2021 ◽

Author(s):

Justina X. Caushi ◽

Jiajia Zhang ◽

Zhicheng Ji ◽

Ajay Vaghasia ◽

Boyang Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

T Cell Receptors ◽

Tumour Microenvironment ◽

Lung Cancers ◽

Cell Receptors ◽

Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

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