Intestinal Lamina Propria Retaining CD4+CD25+ Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation

Makita, Shin; Kanai, Takanori; Nemoto, Yasuhiro; Totsuka, Teruji; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Yamamoto, Masafumi; Kiyono, Hiroshi; Watanabe, Mamoru

doi:10.4049/jimmunol.178.8.4937

Cited by 95 publications

(86 citation statements)

References 23 publications

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“…The lamina propria is known to be the effector site of intestinal immune responses where effector T cell responses (eg., IFN-g production) have been demonstrated to be regulated or down-modulated by Treg cells [31]. We therefore examined the presence of these two cell populations in LP shortly after peroral T. gondii infection.…”

Section: Peroral T Gondii Infection Induces Higher Numbers Of Treg Cmentioning

confidence: 99%

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

Morampudi

Craeye

Moine

et al. 2011

Microbes and Infection

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CD4 þ CD25 þ Foxp3 þ T regulatory (Treg) cells, are known to regulate responses to infectious agents. Here we compared disease progression in BALB/c and C57BL/6(B6) mice infected perorally with Toxoplasma gondii for 7 days and examined the affect of partial depletion of Treg cells in these mice. BALB/c mice were seen to be resistant to peroral infection whereas B6 mice were susceptible in terms of mortality. Although the depletion of Treg cells before infection had no effect on the survival of B6 or BALB/c mice, it resulted in increased parasite burdens in BALB/c mice, especially in the lamina propria, but not in B6 mice. Pro-inflammatory cytokines were also increased in Treg cells depleted BALB/c mice as compared to B6 mice. In addition Treg cell depleted BALB/c mice displayed increased ileal histopathology compared to their non-treated counterparts. These findings provide evidence for the contribution of Treg cells, in the resistance of BALB/c mice against peroral T. gondii infection.

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Section: Peroral T Gondii Infection Induces Higher Numbers Of Treg Cmentioning

confidence: 99%

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

Morampudi

Craeye

Moine

et al. 2011

Microbes and Infection

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“…The most affected area was graded by the severity of lesions. The degree of colonic inflammation was calculated using a previous scoring system (20): mucosa damage, 0; normal, 1; 3-10 intraepithelial cells (IEL)/high power field (HPF) and focal damage, 2; Ͼ10 IEL/HPF and rare crypt abscesses, 3; Ͼ10 IEL/HPF, multiple crypt abscesses and erosion/ulceration, submucosa damage, 0; normal or widely scattered leukocytes, 1; focal aggregates of leukocytes, 2; diffuse leukocyte infiltration with expansion of submucosa, 3; diffuse leukocyte infiltration, muscularis damage, 0; normal or widely scattered leukocytes, 1; widely scattered leukocyte aggregates between muscle layers, 2; leukocyte infiltration with focal effacement of the muscularis, 3; extensive leukocyte infiltration with transmural effacement of the muscularis.…”

Section: Histological Examinationmentioning

confidence: 99%

MyD88-Dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4+ T Cells in Chronic Colitis

Tomita

Kanai

Fujii

et al. 2008

The Journal of Immunology

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TLRs that mediate the recognition of pathogen-associated molecular patterns are widely expressed on/in cells of the innate immune system. However, recent findings demonstrate that certain TLRs are also expressed in conventional TCRαβ+ T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. In this study, we report that in a murine model of chronic colitis induced in RAG-2−/− mice by adoptive transfer of CD4+CD45RBhigh T cells, both CD4+CD45RBhigh donor cells and the expanding colitogenic lamina propria CD4+CD44high memory cells expresses a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs. Although RAG-2−/− mice transferred with MyD88−/−CD4+CD45RBhigh cells developed colitis, the severity was reduced with the delayed kinetics of clinical course, and the expansion of colitogenic CD4+ T cells was significantly impaired as compared with control mice transferred with MyD88+/+CD4+CD45RBhigh cells. When RAG-2−/− mice were transferred with the same number of MyD88+/+ (Ly5.1+) and MyD88−/− (Ly5.2+) CD4+CD45RBhigh cells, MyD88−/−CD4+ T cells showed significantly lower proliferative responses assessed by in vivo CFSE division assay, and also lower expression of antiapoptotic Bcl-2/Bcl-xL molecules and less production of IFN-γ and IL-17, compared with the paired MyD88+/+CD4+ T cells. Collectively, the MyD88-dependent pathway that controls TLR signaling in T cells may directly promote the proliferation and survival of colitogenic CD4+ T cells to sustain chronic colitis.

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“…They were observed for clinical signs of illness [40]: hunched over appearance, piloerection of the coat, diarrhea, and blood in the stool. When mice were killed at a predetermined time point, their clinical score was assessed as the sum (0-8 points) of four parameters: hunching and wasting, 0 or 1; colon thickening, 0-3 (0, no colon thickening; 1, mild thickening; 2, moderate thickening; 3, extensive thickening); stool consistency, 0-3 (0, normal beaded stool; 1, soft stool; 2, diarrhea); and gross blood, 0 or 1 [17].…”

Section: Clinical and Histological Scoringsmentioning

confidence: 99%

“…When mice were killed at a predetermined time point, their clinical score was assessed as the sum (0-8 points) of four parameters: hunching and wasting, 0 or 1; colon thickening, 0-3 (0, no colon thickening; 1, mild thickening; 2, moderate thickening; 3, extensive thickening); stool consistency, 0-3 (0, normal beaded stool; 1, soft stool; 2, diarrhea); and gross blood, 0 or 1 [17]. For the sequential adoptive transfers, we monitored the clinical signs during the observation period, and the ongoing clinical score was defined as the sum (0-5 points) of the above-parameters other than colon thickening [40]. Mice were killed when their ongoing clinical score reached four points or more, and isolated LP CD4 + T cells were transferred into new SCID mice.…”

Section: Clinical and Histological Scoringsmentioning

confidence: 99%

Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis

et al. 2008

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Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4 + cells. However, it remains unknown whether colitogenic CD4 + cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4 + cells, we performed sequential transfers of LP CD4 + cells from colitic CD4 + CD45RB high cell-transferred SCID mice into new SCID mice. Although SCID mice transferred with colitic LP CD4 + cells stably developed colitis until at least the sixth transfer, the interval to the development of colitis gradually lengthened as the number of transfers increased. The incidence of colitis gradually decreased after the seventh transfer. Furthermore, non-colitic LP CD4 + cells from mice transferred over seven times expressed significantly higher levels of PD-1 and produced significantly lower amounts of IFN-c, TNF-a, and IL-17 than colitic LP CD4 + cells recovered after the first transfer. Most notably, we found that re-transfer of non-colitic LP CD4 + cells recovered after multiple transfers prevented the development of colitis in SCID mice co-transferred with CD4 + CD45RB high cells. Thus, colitogenic LP CD4 + cells may be exhausted over time, become non-functional, convert to regulatory cells, and finally suppress colitis in the process of immunosenescence.

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Intestinal Lamina Propria Retaining CD4+CD25+ Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation

Cited by 95 publications

References 23 publications

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

MyD88-Dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4+ T Cells in Chronic Colitis

Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis

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Intestinal Lamina Propria Retaining CD4+CD25+ Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation

Cited by 95 publications

References 23 publications

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

MyD88-Dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4+ T Cells in Chronic Colitis

Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis

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Immunosenescent colitogenic CD4⁺ T cells convert to regulatory cells and suppress colitis