CD4+CD25+Foxp3+ T Cells and CD4+CD25−Foxp3+ T Cells in Aged Mice

Nishioka, Tomohisa; Shimizu, Jun; Iida, Ryuji; Yamazaki, Sayuri; Sakaguchi, Shimon

doi:10.4049/jimmunol.176.11.6586

Cited by 204 publications

(193 citation statements)

References 31 publications

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“…2D) ϩ T cells increases with age (19). The reasons for this increase are unknown but could involve processes similar to those described above, such that some Foxp3 Ϫ T cells are deleted from the repertoire due to reactivity to selfAg, whereas Foxp3 ϩ T cells are spared from deletion to increase in prevalence over time.…”

Section: Foxp3mentioning

confidence: 95%

Cutting Edge: TCR Revision Affects Predominantly Foxp3− Cells and Skews Them toward the Th17 Lineage

Zehn

Bevan

Fink³

2007

The Journal of Immunology

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CD4+ T cells respond to peripheral endogenous superantigen stimulation by undergoing deletion or TCR revision. The latter involves RAG re-expression, TCR gene rearrangement, and expression of a novel TCR. TCR-revised T cells are functional and express a diverse TCR repertoire. Because TCR revision harbors the potential to create self-reactivity, it is important to explore whether T cells known to be self-reactive (regulatory T cells) or those involved in autoimmunity (Th17 cells) arise from TCR revision. Interestingly, we observed that Foxp3+ cells are excluded from revising their TCR and that only a small fraction of postrevision cells expresses Foxp3. In contrast, Th17 cells are 20 times more frequent among revised than among C57BL/6 CD4+ T cells, indicating that postrevision cells are biased toward the Th17 lineage. The link between Th17 differentiation and TCR revision might be highly relevant to the role of Th17 cells in promoting autoimmunity.

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Section: Foxp3mentioning

confidence: 95%

Cutting Edge: TCR Revision Affects Predominantly Foxp3− Cells and Skews Them toward the Th17 Lineage

Zehn

Bevan

Fink³

2007

The Journal of Immunology

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“…Regulatory T cells were shown to accumulate with aging contributing to decrease immune responses. However the augmentation of suppressive function is not due to CD4 + CD25 + Foxp3 + T cells but to CD4 + CD25 -Foxp3+ T cells that appear with aging (Nishioka, Shimizu et al 2006). Since a lack of IL-2 secretion is reported in old individuals, with deficiency in CD4 help, IL-2 treatments were assessed and shown to increase Treg cell numbers in lymphopenic individuals (Zhang, Chua et al 2005).…”

Section: Prevention Of Aging and Immunodepressionmentioning

confidence: 99%

Immunodepression and Immunosuppression During Aging

Thomas‐Vaslin¹,

Six²,

Pham³

et al. 2012

Immunosuppression - Role in Health and Diseases

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“…We found that aged BWF1 mice had substantially increased frequency (Figure 1A) and number ( Figure 1B) of Foxp3 ϩ CD4 ϩ T cells in the lymphoid organs compared with young BWF1 mice. A recent study has shown an age-dependent increase in CD25 Ϫ Foxp3 ϩ CD4 ϩ T cells in 24-month-old normal mice, 25 but increased Foxp3 ϩ CD4 ϩ T cells in aged BWF1 mice was not merely an age-dependent event be- (Figure 2A), CD25 ϩ CD4 ϩ T cells isolated from the spleen and lymph nodes of both young and aged BWF1 mice did not proliferate on stimulation ( Figure 2B) and showed suppressive activity ( Figure 2C). Furthermore, CD25 ϩ CD4 ϩ T cells isolated from the kidney ( Figure 2C) and lung (data not shown), ie, the target organs, of aged BWF1 mice also showed suppressive activity comparable to those from the spleen and lymph nodes.…”

Section: Increased Number and Frequency Of T Reg Cells In Aged Bwf1 Micementioning

confidence: 99%

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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Foxp3 ؉ CD4 ؉ regulatory T (T reg ) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T reg cells in (NZB ؋ NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T reg cells trafficked to target organs because cells were present in the kidney and lung. T reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of costimulatory molecules were also markedly enhanced in the T reg cells of aged BWF1 mice. Furthermore, T reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by a massive production of autoantibodies against various nuclear antigens. The deposit of immune complexes in the target organs, ie, skin, kidney, lung, joints, and central nervous system, is thought to cause fatal dysfunction of the body system. (NZB ϫ NZW) F1 (BWF1) is a mouse strain that has been widely used as a model for SLE since the 1960s. These mice spontaneously develop severe autoimmune disease highly resembling human SLE in terms of serological and hematological abnormalities, and severe nephritis accompanying massive production of antinuclear antibodies. 1 Reconstitution of SCID (severe combined immunodeficiency) mice with cultured pre-B cells of BWF1 mice recapitulates many symptoms of the disease of BWF1 mice. Cultured pre-B cells alone, however, are not sufficient to fully reproduce the disease. 2 These data suggest that cellular subset(s) in addition to B cells are necessary for the development of the lupus-like syndrome of BWF1 mice, although abnormalities of the immune system predominantly lie within B cells. One of the possible candidates is CD4 ϩ T cells, because depletion of CD4 ϩ T cells with anti-CD4 antibody from 5 months old, slightly before the disease onset, prevents the development of the disease. 3,4 CD4 ϩ T cells are, therefore, also required for the development of the disease in BWF1 mice, possibly by providing help for the production of high-affinity autoantibodies.Studies in this decade have clearly shown the key roles of naturally occurring regulatory T (T reg ) cells in the maintenance of dominant self tolerance of the immune system. 5 T reg cells in normal mi...

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CD4+CD25+Foxp3+ T Cells and CD4+CD25−Foxp3+ T Cells in Aged Mice

Cited by 204 publications

References 31 publications

Cutting Edge: TCR Revision Affects Predominantly Foxp3− Cells and Skews Them toward the Th17 Lineage

Cutting Edge: TCR Revision Affects Predominantly Foxp3− Cells and Skews Them toward the Th17 Lineage

Immunodepression and Immunosuppression During Aging

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

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