Chemokines,chemokine receptors and CD4+CD25+ regulatory T cells

The fields of regulatory T (Treg) cells and chemokines/chemokine receptors have progressed rapidly in the last few years. Treg cells, especially CD4⁺CD25⁺ Treg cells, play a critical role in maintaining self-tolerance and immune homeostasis. Chemokines and chemokine receptors are crucial for lymphoid development, homing and immunological regulation. This review will discuss the biological effects of chemokines and chemokine receptors on regulating the migration and development of CD4⁺CD25⁺ Treg cells, and the potential clinical implications of these findings when considering chemokine receptors as therapeutic targets.     

CD73 expression on extracellular vesicles derived from CD4+CD25+Foxp3+ T cells contributes to their regulatory function

CD4⁺CD25⁺Foxp3⁺ Treg cells maintain immunological tolerance. In this study, the possibility that Treg cells control immune responses via the production of secreted membrane vesicles, such as exosomes, was investigated. Exosomes are released by many cell types, including T cells, and have regulatory functions. Indeed, TCR activation of both freshly isolated Treg cells and an antigen‐specific Treg‐cell line resulted in the production of exosomes as defined morphologically by EM and by the presence of tetraspanin molecules LAMP‐1/CD63 and CD81. Expression of the ecto‐5‐nucleotide enzyme CD73 by Treg cells has been shown to contribute to their suppressive function by converting extracellular adenosine‐5‐monophosphate to adenosine, which, following interaction with adenosine receptors expressed on target cells, leads to immune modulation. CD73 was evident on Treg cell derived exosomes, accordingly when these exosomes were incubated in the presence of adenosine‐5‐monophosphate production of adenosine was observed. Most importantly, CD73 present on Treg cell derived exosomes was essential for their suppressive function hitherto exosomes derived from a CD73‐negative CD4⁺ T‐cell line did not have such capabilities. Overall our findings demonstrate that CD73‐expressing exosomes produced by Treg cells following activation contribute to their suppressive activity through the production of adenosine.     

CD8+ CD122+ regulatory T cells contain clonally expanded cells with identical CDR3 sequences of the T‐cell receptor β‐chain

We identified CD8⁺ CD122⁺ regulatory T cells (CD8⁺ CD122⁺ Treg cells) and reported their importance in maintaining immune homeostasis. The absence of CD8⁺ CD122⁺ Treg cells has been shown to lead to severe systemic autoimmunity in several mouse models, including inflammatory bowel diseases and experimental autoimmune encephalomyelitis. The T‐cell receptors (TCRs) expressed on CD8⁺ CD122⁺ Treg cells recognize the target cells to be regulated. To aid in the identification of the target antigen(s) recognized by TCRs of CD8⁺ CD122⁺ Treg cells, we compared the TCR diversity of CD8⁺ CD122⁺ T cells with that of conventional, naive T cells in mice. We analysed the use of TCR‐Vβ in the interleukin 10‐producing population of CD8⁺ CD122⁺ T cells marked by high levels of CD49d expression, and found the significantly increased use of Vβ13 in these cells. Immunoscope analysis of the complementarity‐determining region 3 (CDR3) of the TCR β‐chain revealed remarkable skewing in a pair of Vβ regions, suggesting the existence of clonally expanded cells in CD8⁺ CD122⁺ T cells. Clonal expansion in Vβ13⁺ cells was confirmed by determining the DNA sequences of the CDR3s. The characteristic TCR found in this study is an important building block for further studies to identify the target antigen recognized by CD8⁺ CD122⁺ Treg cells.     

Critical stoichiometric ratio of CD4+ CD25+ FoxP3+ regulatory T cells and CD4+ CD25− responder T cells influence immunosuppression in patients with B‐cell acute lymphoblastic leukaemia

Regulatory T (Treg) cells act to suppress activation of the immune system and thereby maintain immunological homeostasis and tolerance to self-antigens. The frequency and suppressing activity of Treg cells in general are high in different malignancies. We wanted to identify the role and regulation of CD4⁺ CD25⁺ FoxP3⁺ Treg cells in B-cell acute lymphoblastic leukaemia (B-ALL). We have included patients at diagnosis (n = 54), patients in clinical remission (n = 32) and normal healthy individuals (n = 35). These diagnosed patients demonstrated a lower number of CD4⁺ CD25⁺ cells co-expressing a higher level of FoxP3, interleukin-10, transforming growth factor-β and CD152/CTLA-4 than the normal population. Treg cells from patients showed a higher suppressive capability on CD4⁺ CD25⁻ responder T (Tresp) cells than normal. The frequency and immunosuppressive potential of CD4⁺ CD25⁺ FoxP3⁺ Treg cells became high with the progression of malignancy in B-ALL. Relative distribution of Tresp and Treg cells was only ˜5 : 1 in B-ALL but ˜35 : 1 in normal healthy individuals, further confirming the elevated immunosuppression in patients. A co-culture study at these definite ex vivo ratios, indicated that Treg cells from B-ALL patients exhibited higher immunosuppression than Treg cells from normal healthy individuals. After chemotherapy using the MCP841 protocol, the frequency of CD4⁺ CD25⁺ cells was gradually enhanced with the reduction of FoxP3, interleukin-10 positivity corresponded with disease presentation, indicating reduced immunosuppression. Taken together, our study indicated that the CD4⁺ CD25⁺ FoxP3⁺ Treg cells played an important role in immunosuppression, resulting in a positive disease-correlation in these patients. To the best of our knowledge, this is the first detailed report on the frequency, regulation and functionality of Treg cells in B-ALL.     

Inhibition of anti-GD3-ganglioside antibody-induced proliferation of human CD8+ T cells by CD16+ natural killer cells

The ganglioside GD3 has been described as a membrane component of human T cells which is involved in T cell growth. In the present study the activating function of GD3 for human CD4⁺ and CD8⁺ T cells was analyzed by five different monoclonal antibodies (mAb) directed against the GD3 molecule. Three mAb U5, Z21 and R24 induced strong proliferation of peripheral blood mononuclear cells and purified CD8⁺ and CD4⁺ T cells of normal donors containing less than 5% CD16⁺ natural killer (NK) cells. In contrast to CD4⁺ T cells, CD8⁺ T cells proliferated only weakly in the presence of 15% CD16⁺ NK cells. The proliferative response of purified CD4⁺ and CD8⁺ T cells (<5% NK cells) correlated with the antibody-dependent induction of integral and soluble interleukin-2 (IL-2) receptors and was reduced to 20% by an anti-IL-2 receptor antibody. Our results show, that the GD3 molecule represents an activation molecule for both CD4⁺ and CD8⁺ T cells and that CD16⁺ NK cells selectively inhibit anti-GD3 antibody-induced proliferation of CD8⁺ T cells.     

Circulating CD137+CD8+ T cells accumulate along with increased functional regulatory T cells and thoracic tumour burden in lung cancer patients

CD137 is a promising target for immunostimulation strategies against cancer. Previous studies showed that CD137⁺CD8⁺ T cells are enriched in antitumour effector T cells in both preclinical tumour models and cancer patients, but to date, such T cells in the blood of lung cancer patients have not been sufficiently investigated. In this study, circulating antigen‐activated CD8⁺ T cell subsets, identified as CD137⁺CD8⁺ or PD‐1⁺ (programmed cell death protein 1) CD8⁺, and regulatory T cells (Treg), identified as CD4⁺CD25⁺CD127^low/?, in 40 untreated lung cancer patients and in 49 age‐ and sex‐matched healthy controls (HCs) were assessed by flow cytometry. Results were evaluated for associations with lung cancer patient clinical characteristics. Correlations between antigen‐activated CD8⁺ T cells and effector Treg (CTLA‐4⁺ [cytotoxic T‐lymphocyte antigen 4] CD4⁺CD25⁺CD127^low/?) were also investigated. Higher percentages of PD‐1⁺, CD137⁺ and PD‐1⁺CD137⁺ amongst CD8⁺ T cells were observed in lung cancer patients compared with HCs. The percentages of CD137⁺CD8⁺ and PD‐1⁺CD137⁺CD8⁺ T cell subsets amongst CD8⁺ T cells were positively correlated with thoracic tumour burden and were strongly positively correlated with the percentage of effector Treg subset. Smoking patients harboured higher percentages of the PD‐1⁺CD8⁺ T cell subset compared with non‐smoking patients. This study demonstrated that circulating antigen‐activated CD8⁺ T cells accumulated in lung cancer patients along with increased effector Treg and thoracic tumour burden. These findings aid a better understanding of immune‐host interactions in lung cancer patients using peripheral blood, and further support immunotherapeutic intervention strategies using combination therapy for differential control of Treg and activation of tumour‐specific effector T cells.     

Mouse and human CD8+ CD28low regulatory T lymphocytes differentiate in the thymus

Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co‐receptor and low levels of the co‐stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8⁺ CD28^low Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28^low phenotype. We demonstrate that functional CD8⁺ CD28^low Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8⁺ CD28^low Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8⁺ CD28^low Treg cells develop simultaneously with CD8⁺ CD28^high conventional T cells. We also identified a novel homologous naive CD8⁺ CD28^low T‐cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8⁺ CD28^low cells can develop in the thymus of mice and suggest that the same is true in humans.     

Annexin V expression on CD4+ T cells with regulatory function

Regulatory T (Treg) cells induce immunologic tolerance by suppressing effector functions of conventional lymphocytes in the periphery. On the other hand, immune silencing is mediated by recognition of phosphatidylserine (PS) on apoptotic cells by phagocytes. Here we describe expression of the PS-binding protein Annexin V (ANXA5) in CD4⁺ CD25^hi Treg cells at the mRNA and protein levels. CD4⁺ ANXA5⁺ T cells constitute about 0·1%–0·6% of peripheral blood CD3⁺ T cells, exhibit co-expression of several Treg markers, such as Forkhead box P3, programmed cell death protein-1, cytotoxic T-lymphocyte antigen-4 and CD38. In vitro, ANXA5⁺ Treg cells showed enhanced adhesion to PS⁺ endothelial cells. Stimulated by anti-CD3 and PS⁺ syngeneic antigen-presenting cells CD4⁺ ANXA5⁺ T cells expanded in the absence of exogenous interleukin-2. CD4⁺ ANXA5⁺ T cells suppressed CD4⁺ ANXA5⁻ T-cell proliferation and mammalian target of rapamycin phosphorylation, partially dependent on cell contact. CD4⁺ ANXA5⁺ T-cell-mediated suppression was allo-specific and accompanied by an increased production of anti-inflammatory mediators. In vivo, using a model of delayed type hypersensitivity, murine CD4⁺ ANXA5⁺ T cells inhibited T helper type 1 responses. In conclusion, we report for the first time expression of ANXA5 on a subset of Treg cells that might bridge classical regulatory Treg function with immune silencing.     

Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg

The importance of CD8⁺CD122⁺ Treg in the maintenance of immune homeostasis has been previously demonstrated in mice. Because the expression pattern of CD8 and CD122 in humans is different from that in mice, human CD8⁺ Treg that correspond to the murine CD8⁺CD122⁺ Treg have not been identified. In this study, we performed DNA microarray analyses to compare the gene expression profiles of CD8⁺CD122⁺ cells and CD8⁺CD122^? cells in mice and found that CXCR3 was preferentially expressed in CD8⁺CD122⁺ cells. When we analyzed the expression of CD122 and CXCR3 in murine CD8⁺ cells, we observed a definite population of CD122⁺CXCR3⁺ cells. CD8⁺CXCR3⁺ cells in mice showed similar regulatory activities to CD8⁺CD122⁺ cells by in vivo and in vitro assays. While CD8⁺CD122⁺CXCR3⁺ cells are present in mice, CD8⁺CXCR3⁺ cells, but not CD8⁺CD122⁺ cells, are present in humans. In the in vitro assay, human CD8⁺CXCR3⁺ cells showed the regulatory activity of producing IL‐10 and suppressing IFN‐γ production from CD8⁺CXCR3^? cells. These results suggest that human CD8⁺CXCR3⁺ T cells are the counterparts of murine CD8⁺CD122⁺ Treg.     

Mapping urinary chemokines in human lupus nephritis: Potentially redundant pathways recruit CD4+ and CD8+ T cells and macrophages

Renal infiltration of inflammatory cells contributes to the pathogenesis of lupus nephritis (LN). Current knowledge on the recruitment mechanisms relies mainly on findings in rodent models. Here, we assess various chemokine pathways in human LN by comparing urinary chemokine concentrations (in 25 patients with acute LN and in 78 lupus patients without active LN) with the expression of corresponding chemokine receptors on urinary leukocytes (in ten acute LN patients). Nine urinary chemokines were significantly elevated in LN patients and correlated with renal disease activity and urinary cell counts; however, their concentrations displayed considerable interindividual heterogeneity. Analysis of the corresponding receptors revealed abundance of urinary CD8⁺ T cells for CCR5 and CXCR3, while CD4⁺ T cells were additionally enriched for CCR1, CCR6 and CXCR6. Urinary Treg showed similar CCR expression, and urinary CD14⁺ macrophages were enriched for CCR5 expressing cells. In conclusion, cell specific recruitment patterns seem to involve CCR5 and CXCR3 in all cells studied, while CD4⁺ T‐cell subset recruitment is probably much more varied. However, urinary chemokine abundance in active LN is individually variable in our cohort and does not offer a singular chemokine usable as universal biomarker or potential future treatment target.     

Flt3 ligand expands CD4+FoxP3+ regulatory T cells in human subjects

CD4⁺CD25⁺FoxP3⁺ naturally occurring regulatory T (Treg) cells play a crucial role in the maintenance of immune tolerance and in preventing autoimmune pathology. Interventions that expand Treg cells are highly desirable, as they may offer novel treatment options in a variety of autoimmune and transplantation settings. Paralleling previous preclinical studies, we demonstrate here that administration of the hematopoietic growth factor Flt3L to human subjects increases the frequency and absolute number of Treg cells, and reduces the ratio of CD8⁺ T cells to Treg cells in the peripheral blood. The increase in Treg cells was due to enhanced Treg‐cell proliferation rather than release of Treg cells from the thymus. Further studies revealed that Flt3L‐induced proliferation of Treg cells was an indirect effect that occurred via the interaction of Treg cells with the Flt3L‐expanded pool of CD1c⁺ myeloid dendritic cells. On the basis of these findings, Flt3L may represent a promising agent for promoting immune tolerance in a variety of clinical settings.     

Co‐expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood

Previously, we found that co‐expression of CD25 and TNFR2 identified the most suppressive subset of mouse Treg. In this study, we report that human peripheral blood (PB) FOXP3⁺ cells present in CD25^high, CD25^low and even CD25^– subsets of CD4⁺ cells expressed high levels of TNFR2. Consequently, TNFR2‐expressing CD4⁺CD25 ⁺ Treg included all of the FOXP3⁺ cells present in the CD4⁺CD25^high subset as well as a substantial proportion of the FOXP3⁺ cells present in the CD4⁺CD25^low subset. Flow cytometric analysis of PB identified five‐fold more Treg, determined by FOXP3 expression, in the CD4⁺CD25⁺TNFR2⁺ subset than in the CD4⁺CD25^high subset. In addition, similar levels of FOXP3⁺ cells were identified in both the CD4⁺CD25⁺TNFR2⁺ and CD4⁺CD25⁺CD127^low/? subsets. Furthermore, the CD4⁺CD25⁺TNFR2⁺ subset expressed high levels of CTLA‐4, CD45RO, CCR4 and low levels of CD45RA and CD127, a phenotype characteristic of Treg. Upon TCR stimulation, human PB CD4 ⁺ CD25 ⁺ TNFR2 ⁺ cells were anergic and markedly inhibited the proliferation and cytokine production of co‐cultured T‐responder cells. In contrast, CD4 ⁺ CD25 ⁺ TNFR2 ^– and CD4 ⁺ CD25 ^– TNFR2 ⁺ T cells did not show inhibitory activity. As some non‐Treg express TNFR2, the combination of CD25 and TNFR2 must be used to identify a larger population of human Treg, a population that may prove to be of diagnostic and therapeutic benefit in cancer and autoimmune diseases.     

CD4+ CD25+ Treg regulate the contribution of CD8+ T-cell subsets in repopulation of the lymphopenic environment

Peripheral T‐cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T‐cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8⁺ central‐memory T cells (T_CM) and effector‐memory T cells (T_EM) pools after adoptive transfer of sorted CD8⁺ T cells from naïve, T_CM and T_EM subsets into T‐cell‐deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8⁺ T‐cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4⁺CD25⁺ Treg play a major role in the repopulation of the CD8⁺ T‐cell pool and that CD8⁺ T‐cell subsets impact on each other. In the absence of CD4⁺CD25⁺ Treg, a small fraction of naïve CD8⁺ T cells strongly proliferates, correlating with further expansion and differentiation of co‐expanding CD8⁺ T cells. CD4⁺CD25⁺ Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered T_CM and T_EM fractions, and leading to repopulation of each pool with progeny of its own kind.     

CD155/CD226‐interaction impacts on the generation of innate CD8+ thymocytes by regulating iNKT‐cell differentiation

The cell surface receptor CD155 influences a variety of immune processes by binding to its ligands CD226, CD96, or TIGIT. Here, we report that the interaction of CD155 with CD226 in the thymus of BALB/c mice has a dual function. It directly influences the dwell time of memory‐like CD8⁺ T cells, while it is indirectly involved in generating these cells. It was shown earlier that a massive emergence of memory‐like CD8 T cells in thymus crucially depends on abundant IL‐4, secreted in steady state by iNKT2 (where iNKT is invariant NKT) cells, a subclass of iNKT cells. Here, we show that absence of either CD155 or CD226 in BALB/c mice causes a profound shift in the iNKT subtype composition in thymus, expanding the frequency and numbers of iNKT1 cells at the expense of iNKT2 cells, as well as iNKT17 cells. This shift results in a drop of available IL‐4 and creates a scenario similar to that observed in C57BL/6 mice, where iNKT1 cells predominate and iNKT2 cells are much less frequent when compared with BALB/c mice. Yet also in C57BL/6 mice, lack of CD155 or CD226 provokes a further decline in iNKT2 cells, suggesting that the observed effects are not restricted to a particular inbred strain.     

Renal‐infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40–60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus‐prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus‐prone mouse models, we showed the pathogenic role of a kidney‐infiltrating CD11c⁺ myeloid cell population in LN. These CD11c⁺ cells accumulated in the kidneys of lupus‐prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C)^low mature monocytes. The cytokine/chemokine profile of these renal‐infiltrating CD11c⁺ cells suggests their roles in promoting LN, which was confirmed further in a loss‐of‐function in‐vivo study by using an antibody‐drug conjugate (ADC) strategy targeting CX₃CR1, a chemokine receptor expressed highly on these CD11c⁺ cells. However, CX₃CR1 was dispensable for the homing of CD11c⁺ cells into lupus nephritic kidneys. Finally, we found that these CD11c⁺ cells co‐localized with infiltrating T cells in the kidney. Using an ex‐ vivo co‐culture system, we showed that renal‐infiltrating CD11c⁺ cells promoted the survival, proliferation and interferon‐γ production of renal‐infiltrating CD4⁺ T cells, suggesting a T cell‐dependent mechanism by which these CD11c⁺ cells promote LN. Together, our results identify a pathogenic kidney‐infiltrating CD11c⁺ cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN.     

CD39 is involved in mediating suppression by Mycobacterium bovis BCG‐activated human CD8+CD39+ regulatory T cells

Regulatory T (Treg) cells can balance normal tissue homeostasis by limiting inflammatory tissue damage, e.g. during pathogen infection, but on the other hand can also limit protective immunity induced during natural infection or following vaccination. Because most studies have focused on the role of CD4⁺ Treg cells, relatively little is known about the phenotype and function of CD8⁺ Treg cells, particularly in infectious diseases. Here, we describe for the first time the expression of CD39 (E‐NTPDase1) on Mycobacterium‐activated human CD8⁺ T cells. These CD8⁺CD39⁺ T cells significantly co‐expressed the Treg markers CD25, Foxp3, lymphocyte activation gene‐3 (LAG‐3), and CC chemokine ligand 4 (CCL4), and suppressed the proliferative response of antigen‐specific CD4⁺ T helper‐1 (Th1) cells. Pharmacological or antibody mediated blocking of CD39 function resulted in partial reversal of suppression. These data identify CD39 as a novel marker of human regulatory CD8⁺ T cells and indicate that CD39 is functionally involved in suppression by CD8⁺ Treg cells.     

CD8+ Tregs revisited: A heterogeneous population with different phenotypes and properties

Regulatory T cells (Tregs) play a key role in the peripheral self-tolerance and preventing autoimmunity. While classical CD4⁺ Foxp3⁺ Tregs are well established, their CD8⁺ counterparts are still controversial in many aspects including their phenotypic identity and their mechanisms of suppression. Because of these controversies and because of only a limited number of studies documenting the immunoregulatory function of CD8⁺ Tregs in vivo, the concept of CD8⁺ Tregs is still not unanimously accepted. We propose that any T-cell subset considered as true regulatory must be distinguishable from other cell types and must suppress in vivo immune responses via a known mechanism. In this article, we revisit the concept of CD8⁺ Tregs by focusing on the characterization of individual CD8⁺ T-cell subsets with proposed regulatory capacity separately. Therefore, we review the phenotype and function of CD8⁺ FOXP3⁺ T cells, CD8⁺ CD122⁺ T cells, CD8⁺ CD28^low/− T cells, CD8⁺ CD45RC^low T cells, T cells expressing CD8αα homodimer and Qa-1-restricted CD8⁺ T cells to show whether there is sufficient evidence to establish these subsets as bona fide Tregs. Based on the intrinsic ability of CD8⁺ Treg subsets to promote immune tolerance in animal models, we elaborate on their potential use in clinics.     

Critical role of CCL22/CCR4 axis in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α+ CD103+ dendritic cells

Macrophages and dendritic cells (DCs) in murine spleen are essential for the maintenance of immune homeostasis by elimination of blood‐borne foreign particles and organisms. It has been reported that splenic DCs, especially CD8α⁺ CD103⁺ DCs, are responsible for tolerance to apoptosis‐associated antigens. However, the molecular mechanism by which these DCs maintain immune homeostasis by blood‐borne apoptotic cell clearance remains elusive. Here, we found that the CCL22/CCR4 axis played a critical role in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α⁺ CD103⁺ DCs. The present results revealed that systemic administration of apoptotic cells rapidly induced a large number of CCL22 and CCR4⁺ regulatory T (Treg) cells in the spleen of C57BL/6J mice. Further study demonstrated that CD8α⁺ CD103⁺ DCs dominantly produce much higher CCL22 than CD8α⁺ CD103^? DCs. Moreover, the transient deletion of CD8α⁺ CD103⁺ DCs caused a decrease in CCL22 levels together with CCR4⁺ Treg cell percentage. Subsequently, the levels of some pro‐inflammatory cytokines, such as interleukin‐17 and interferon‐γ in the spleen with the absence of CD8α⁺ CD103⁺ DCs increased in response to the administration of apoptotic cells. Hence, intravenous injection of apoptotic cells induced a subsequent increase in CCL22 expression and CCR4⁺ Treg cells, which contribute to the maintenance of immune homeostasis at least partially by splenic CD8α⁺ CD103⁺ DCs.     

CD4+ CD25+ GARP+ regulatory T cells display a compromised suppressive function in patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a lethal inflammatory heart disease and closely connected with dysfunction of the immune system. Glycoprotein A repetitions predominant (GARP) expressed on activated CD4⁺ T cells with suppressive activity has been established. This study aimed to investigate the frequency and function of circulating CD4⁺   CD25⁺ GARP⁺ regulatory T (Treg) cells in DCM. Forty‐five DCM patients and 46 controls were enrolled in this study. There was a significant increase in peripheral T helper type 1 (Th1) and Th17 number and their related cytokines [interferon‐γ (IFN‐γ), interleukin (IL‐17)], and an obvious decrease in Treg number, transforming growth factor‐β₁ (TGF‐β₁) levels and the expression of forkhead box P3 (FOXP3) and GARP in patients with DCM compared with controls. In addition, the suppressive function of CD4⁺ CD25⁺ GARP⁺ Treg cells was impaired in DCM patients upon T‐cell receptor stimulation detected using CFSE dye. Lower level of TGF‐β₁ and higher levels of IFN‐γ and IL‐17 detected using ELISA were found in supernatants of the cultured CD4⁺ CD25⁺ GARP⁺ Treg cells in DCM patients compared with controls. Together, our results indicate that CD4⁺ CD25⁺ GARP⁺ Treg cells are defective in DCM patients and GARP seems to be a better molecular definition of the regulatory phenotype. Therefore, it might be an attractive stategy to pay more attention to GARP in DCM patients.