Paradoxical Effect of Reduced Costimulation in T Cell-Mediated Colitis

Kim, Gisen; Levin, Matthew; Schoenberger, Stephen P.; Sharpe, Arlene H.; Kronenberg, Mitchell

doi:10.4049/jimmunol.178.9.5563

Cited by 11 publications

(17 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The colitis model induced by the transfer of CD4 + CD45RB high cells to immune deficient mice has been often used to test the roles of CD4 T lymphocytes in inducing or preventing intestinal inflammation (22-24). The transferred T lymphocytes undergo expansion driven by the recognition of antigens from the microbial flora, and they differentiate into pathogenic T helper cells (25, 26).…”

Section: Resultsmentioning

confidence: 99%

A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes

Kim

Shinnakasu

Saris

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

IL-27, an IL-12 family cytokine, has pleiotropic functions in the differentiation and expansion of CD4+ T cell subsets. Here, we discovered a novel function of IL-27. CD4+CD45RBhigh T cells from mice deficient for the α chain of IL-27 receptor failed to induce colitis in Rag−/− recipients, because of an inability of activated donor cells to survive. Interestingly, IL-27 was indispensable for prevention of colitis by regulatory T cells, also because of a defect in long-term cell survival. IL-27 affected the survival of activated T lymphocytes, rather than promoting cell proliferation, by inhibiting Fas-mediated activation-induced T cell death, acting through the STAT3 signaling pathway. The addition of IL-27 during activation resulted in an increased cell number, which was correlated with decreased activation of both caspases 3 and 8. This pro-survival effect was attributed to downregulation of FasL, as well as to the induction of the anti-apoptotic protein cFLIP. While activation induced cell death is an important mechanism for the maintenance of immunological homeostasis, protection of lymphocytes from excessive cell death is essential for effective immunity. Our data indicate that IL-27 plays a crucial role in the inhibition of activation-induced cell death, thereby permitting antigen-driven T cell expansion.

show abstract

Section: Resultsmentioning

confidence: 99%

A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes

Kim

Shinnakasu

Saris

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, inhibition of IL-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi , while CD28 deficiency exacerbates joint inflammation upon Borrelia burgdorferi infection, resulting in the development of chronic Lyme arthritis [45], [46], [47]. Finally, reduced co-stimulation in either B7.1 or B7.2-deficient recipients resulted in a dramatic acceleration of colitis induction following transfer of CD4 + CD45RB high cells [48], [49]. Recently, the efficacy of CTLA4-Ig has been investigated in human clinical trials to prevent transplant rejection, and in the treatment of RA and psoriasis vulgaris [50].…”

Section: Discussionmentioning

confidence: 99%

CD28 Co-Stimulation Down Regulates Th17 Development

et al. 2009

View full text Add to dashboard Cite

Th17 cells are implicated in host defence and autoimmune diseases. CD28/B7 co-stimulation is involved in the induction and progression of autoimmune diseases, but its role in controlling murine Th17 cell fate remains to be clarified. We here report that soluble anti-CD28 mAb suppressed the differentiation of anti-CD3-stimulated naïve CD4+ T cells into IL-17-producing cells. CD28 co-stimulation reduced the frequency of proliferating cells that produce IL-17. We provide evidence for an IL-2 and IFN-γ-dependent mechanism of CD28-mediated IL-17 suppression. CD28 blockade of Th17 development was correlated with a decrease rather than an increase in the percentage of Foxp3+ T cells. In APC/T cell co-cultures, mature dendritic cells (DC) were less efficient than immature DC in their ability to support Th17 cell differentiation, while CTLA4-Ig, an agent blocking CD28/B7 and CTLA4/B7 interactions, facilitated both murine and human Th17 differentiation. This study identifies the importance of B7 co-stimulatory molecules in the negative regulation of Th17 development. These unexpected results caution targeting the CD28/B7 pathways in the treatment of human autoimmune diseases.

show abstract

“…Sections (4 μm) were used for H&E staining. Histologic assessment was performed in a blinded fashion using a scoring system previously described (51). Briefly, a numerical scale was used to denote the severity of inflammation (0, none; 1, mild; 2, moderate; and 3, severe), the level of involvement (0, none; 1, mucosa; 2, mucosa and submucosa; and 3, transmural), and extent of epithelial/crypt damage (0, none; 1, basal 1/3; 2, basal 2/3; 3, crypt loss; 4, crypt and surface epithelial destruction).…”

Section: Methodsmentioning

confidence: 99%

β-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells

et al. 2014

View full text Add to dashboard Cite

The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of TH17 cells and inflammation predict poor outcome, while infiltration by Tregs that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become pro-inflammatory and tumor promoting. These properties were directly linked with their expression of RORγt, the signature transcription factor of TH17 cells. Here, we report that Wnt/β-catenin signaling in T-cells promotes expression of RORγt. Expression of β-catenin was elevated in T-cells and Tregs of patients with colitis and colon cancer. Genetically engineered activation of β-catenin in mouse T-cells resulted in enhanced chromatin accessibility in the proximity of Tcf-1 binding sites genome-wide, induced expression of TH17 signature genes including RORγt, and promoted TH17-mediated inflammation. Strikingly, the mice had inflammation of intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. Based on these findings we conclude that activation of Wnt/β-catenin signaling in T-cells and/or Tregs is causatively linked with the imprinting of pro-inflammatory properties and the promotion of colon cancer.

show abstract

Paradoxical Effect of Reduced Costimulation in T Cell-Mediated Colitis

Cited by 11 publications

References 51 publications

A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes

A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes

CD28 Co-Stimulation Down Regulates Th17 Development

β-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells

Contact Info

Product

Resources

About