Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise — both acute and chronic — exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.

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The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease

The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.

https://www.nefro.cl/DOCS/evento1/papers/The%20immune%20system%20and%20kidney.%20nature%20reviews.pdf

The immune system and kidney disease: basic concepts and clinical implications

Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection. Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction of these cell types is complex and incompletely understood, and the same is true of their interplay and relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss the common and distinct characteristics of DCs and macrophages, as well as key advances that have identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority for further investigation, and highlight the prospects for translational and therapeutic application of the knowledge acquired.

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Dendritic cells and macrophages in the kidney: a spectrum of good and evil

Forkhead box P3(FOXP3) is known as the optimum maker for regulatory T cells(Tregs), which are conventionally thought to induce immune tolerance to disturb the antitumor immunity. However, the research on the prognostic significance of tumor-infiltrating FOXP3+ Tregs in breast cancer is still limited and the results are controversial. We searched for studies in PubMed, EMBASE and Web of Science prior to January 2015. The correlation between FOXP3+ tumor-infiltrating lymphocytes(TILs) and breast cancer prognosis was analyzed. The meta-analysis was performed using STATA 11.0. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were used to estimate the degree of the association between FOXP3+ TILs and prognosis of breast cancers, while relative ratios (RRs) were used to evaluate the relationship between FOXP3+ TILs and clinicopathological features of breast cancers. A total of 15 studies comprising 8666 breast cancer patients met the inclusion criteria. Our results showed that higher FOXP3+ TILs level was significantly associated with poor prognosis in terms of overall survival (OS) (pooled HR:1.60, 95 % CI:1.06–2.42; P < 0.05). We found that breast cancer with higher FOXP3+ TILs level was positively correlated with c-erbB-2 positive status (pooled RR:1.52, 95 % CI:1.32–1.75; P < 0.05), lymph node positive status(pooled RR:1.17, 95 % CI:1.04–1.32; P < 0.05) while there was a negative association with ER positive status(pooled RR:0.65, 95 % CI:0.56–0.76; P < 0.05) and PR positive status(pooled RR:0.66, 95 % CI:0.51–0.87; P < 0.05). The present results of meta-analysis showed that higher FOXP3+ TILs level in patients with breast cancer led to poor overall survival (OS) and was significantly associated with c-erbB-2 status, lymph node status, ER status and PR status. FOXP3+ TILs level is a promising prognostic factor in breast cancer.

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Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs : a systematic review and meta-analysis

https://www.kidney-international.org/article/S0085-2538(15)55008-4/pdf

Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis

Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10–producing Foxp3 + T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3 + TregseliminatedtheabilityofthesecellstosuppressrenalandsystemicproductionofIFNgandIL17; these IL-10–deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.

/pdf/regulatory-t-cell-derived-il-10-ameliorates-crescentic-gn-32lat9ax2i.pdf

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN) are driven by inappropriately regulated cellular and humoral immune responses subsequently leading to renal tissue injury. Recent studies demonstrated the crucial role for regulatory T cells (Tregs) in suppressing pathogenic T-cell responses during nephrotoxic nephritis (NTN), a murine model of cGN. However, mechanisms of immune regulation in cGN are less clear. Here, we aim at investigating the role of the co-inhibitory PD-1/PD-L1 pathway in Treg-mediated suppression of renal inflammation. We demonstrated that Foxp3+ Tregs expressing PD-L1 infiltrate the kidney during NTN. Inhibition of PD-L1 signalling by using PD-L1−/− mice or by blockage of PD-L1 in wildtype mice resulted in an increased Treg frequency in the inflamed kidney. However, mice lacking PD-L1 developed more severe NTN associated with an elevated pathogenic renal Th1 immune response, which was reversed by blockage of IFNγ in these mice. Interestingly, lack of PD-L1 altered the gene expression profile of Tregs in homeostasis and kidney inflammation. Functionally, Tregs from nephritic PD-L1−/− mice had impaired suppressive capacity in vitro and failed to protect from NTN in vivo. Thus, PD-L1 displays a protective role in NTN, which is related to Treg-mediated suppression of the Th1 immune response.

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The co-inhibitory molecule PD-L1 contributes to regulatory T cell-mediated protection in murine crescentic glomerulonephritis

IL-10-secreting regulatory B cells have been postulated as negative mediators of inflammation However, their impact on immune-mediated diseases requires further investigation We recently found that IL-10-secreting B cells infiltrate the kidney during crescentic glomerulonephritis (GN) We therefore studied the function of B-cell-derived IL-10 in light of the potential risks associated with increasingly used B-cell depleting therapies Lack of IL-10 production by B cells, however, did not influence acute or adaptively mediated progressive renal injury in terms of renal function and histological damage in the nephrotoxic nephritis model of GN Renal leukocyte infiltration and cytokine expression were similar apart from increased macrophages in mice lacking B-cell-derived IL-10 Systemic immune responses as assessed by cytokine production, leukocyte composition, proliferation, and activation were indistinguishable, while production and renal deposition of Ag-specific IgG were mildly impaired in the absence of B-cell-produced IL-10 Importantly, detailed analysis of systemic and renal regulatory T cells did not show any differences between nephritic mice bearing IL-10-deficient B cells and WT controls Finally, studies in reporter mice revealed that B cells are only a minor source of systemic IL-10 In summary, our data reveal that endogenous B-cell-derived IL-10 does not play a major role in the nephrotoxic nephritis model of crescentic GN

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.201343842

Annett Ostmann

Papers

Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

The co-inhibitory molecule PD-L1 contributes to regulatory T cell-mediated protection in murine crescentic glomerulonephritis

B‐cell‐derived IL‐10 does not vitally contribute to the clinical course of glomerulonephritis