T Cell Transfer Model of Colitis: A Great Tool to Assess the Contribution of T Cells in Chronic Intestinal Inflammation

The gut microbiome is the largest source of intrinsic non–self-antigens that are continuously sensed by the immune system but typically do not elicit lymphocyte responses. CD4+ T cells are critical to sustain uninterrupted tolerance to microbial antigens and to prevent intestinal inflammation. However, clinical interventions targeting commensal bacteria–specific CD4+ T cells are rare, because only a very limited number of commensal-derived epitopes have been identified. Here, we used a new approach to study epitopes and identify T cell receptors expressed by CD4+Foxp3+ (Treg) cells specific for commensal-derived antigens. Using this approach, we found that antigens from Akkermansia muciniphila reprogram naïve CD4+ T cells to the Treg lineage, expand preexisting microbe specific Tregs, and limit wasting disease in the CD4+ T cell transfer model of colitis. These data suggest that the administration of specific commensal epitopes may help to widen the repertoire of specific Tregs that control intestinal inflammation.

Download Full-text

P032 MiR-511 deficiency aggravates T cell transfer colitis in mice

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.161 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S147-S147

Author(s):

S Rahman ◽

A Elfiky ◽

P H P van Hamersveld ◽

C Verseijden ◽

O Welting ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Intestinal Inflammation ◽

Activity Index ◽

Disease Activity Index ◽

Cell Populations ◽

Spleen Weight ◽

Cell Transfer ◽

Rag 1 ◽

T Cell Transfer

Abstract Background MiR-511 is embedded in intron region 5 of the CD206/MRC1 gene, expressed by macrophage and dendritic cell populations. In this study, we aimed to investigate the effect of MiR-511 deficiency on intestinal inflammation in a murine T cell transfer colitis model. Methods A double MiR-511- and Rag-1 (knockout) KO mouse was generated and a T cell transfer colitis was induced by intraperitoneal injection of naïve T cells from donor WT mice. Since these mice lack mature T and B cells, first signs of inflammation appeared at week 3 after T cell injection. An endoscopy score was obtained to determine inflammation at week 3 and 5, respectively. The experiment was terminated at week 5 and severity of inflammation was assessed on the basis of weight loss, colon weight/length ratio, histology score, spleen weight and disease activity index. In addition, flow cytometry was performed for analysing immune cell populations (monocyte, macrophages, dendritic cells, neutrophils) in the colons of both control and colitis groups and T cells in the spleens of colitis group, respectively. Results Following the induction of T cell transfer colitis, colon weight/length ratio, spleen weight and endoscopic score were significantly increased in the double KO mice compared to Rag-1 KO control mice. A higher histology score and disease activity index in the double KO with no change in weight loss compared to Rag-1 KO control mice was observed. A significant increase in monocyte population in the colons of double KO was seen and increased numbers of monocytes was also observed in the double KO control group with no inflammation. Also, a higher influx of T cells in the double KO mice with a significant increase in Foxp3 and IL4 population was observed in the group with colitis. Conclusion MiR-511 deficiency aggravates intestinal inflammation compared to Rag-1 KO control mice. Also, a higher presence of monocyte as well as T cell populations were observed in these mice. Together these data show that MiR-511 is involved in the regulation of intestinal health. Future research will focus on underlying mechanisms.

Download Full-text

Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00071.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. G754-G760 ◽

Cited By ~ 10

Author(s):

N. Dan ◽

T. Kanai ◽

T. Totsuka ◽

R. Iiyama ◽

M. Yamazaki ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lamina Propria ◽

Fas Ligand ◽

Intestinal Inflammation ◽

Therapeutic Effects ◽

Cell Transfer ◽

Chronic Colitis ◽

Wasting Disease ◽

T Cell Transfer

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-γ production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-α and IL-1β production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.

Download Full-text

Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

PLoS ONE ◽

10.1371/journal.pone.0119885 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0119885 ◽

Cited By ~ 3

Author(s):

Nicole V. Acuff ◽

Xin Li ◽

Rebecca Kirkland ◽

Tamas Nagy ◽

Wendy T. Watford

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Progression ◽

Cd4 T Cells ◽

Transfer Model ◽

Cell Transfer ◽

T Cell Transfer

Download Full-text

T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90462.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. G135-G146 ◽

Cited By ~ 238

Author(s):

Dmitry V. Ostanin ◽

Jianxiong Bao ◽

Iurii Koboziev ◽

Laura Gray ◽

Sherry A. Robinson-Jackson ◽

...

Keyword(s):

T Cell ◽

Intestinal Inflammation ◽

Transfer Model ◽

Cell Transfer ◽

Chronic Colitis ◽

Immunological Mechanisms ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

T Cell Transfer ◽

Detailed Protocol

The inflammatory bowel diseases (Crohn's disease; ulcerative colitis) are idiopathic chronic inflammatory disorders of the intestine and/or colon. A major advancement in our understanding of the pathogenesis of these diseases has been the development of mouse models of chronic gut inflammation. One model that has been instrumental in delineating the immunological mechanisms responsible for the induction as well as regulation of intestinal inflammation is the T cell transfer model of chronic colitis. This paper presents a detailed protocol describing the methods used to induce chronic colitis in mice. Special attention is given to the immunological concepts that explain disease pathogenesis in this model, considerations and potential pitfalls in using this model, and finally different “tricks” that we have learned over the past 12 years that have allowed us to develop a more simplified version of this model of experimental IBD.

Download Full-text

Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003633 ◽

2022 ◽

Vol 10 (1) ◽

pp. e003633

Author(s):

Jiemiao Hu ◽

Qing Yang ◽

Wendong Zhang ◽

Hongwei Du ◽

Yuhui Chen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Membrane ◽

Cell Therapy ◽

Solid Tumors ◽

Cell Transfer ◽

T Cell Therapy ◽

A Cell ◽

T Cell Transfer ◽

Heterogeneous Solid

BackgroundAdoptive T-cell transfer has become an attractive therapeutic approach for hematological malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) exhibits potent antitumor efficacy against solid tumors, but its clinical application has been stalled because of toxicity. Here, we aimed to develop a safe approach to IL-12 T-cell therapy for eliminating large solid tumors.MethodsWe generated a cell membrane-anchored IL-12 (aIL12), a tumor-targeted IL-12 (ttIL12), and a cell membrane-anchored and ttIL-12 (attIL12) and a cell membrane-anchored and tumor-targeted ttIL-12 (attIL12) armed T cells, chimeric antigen receptor-T cells, and T cell receptor-T (TCR-T) cells with each. We compared the safety and efficacy of these armed T cells in treating osteosarcoma patient-derived xenograft tumors and mouse melanoma tumors after intravenous infusions of the armed T cells.ResultsattIL12-T cell infusion showed remarkable antitumor efficacy in human and mouse large solid tumor models. Mechanistically, attIL12-T cells targeted tumor cells expressing cell-surface vimentin, enriching effector T cell and interferon γ production in tumors, which in turn stimulates dendritic cell maturation for activating secondary T-cell responses and tumor antigen spreading. Both attIL12- and aIL12-T-cell transfer eliminated peripheral cytokine release and the associated toxic effects.ConclusionsThis novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.

Download Full-text