Increased CTLA‐4+ T cells may contribute to impaired T helper type 1 immune responses in patients with chronic obstructive pulmonary disease

Impaired T helper type 1 (Th1) function is implicated in the susceptibility of patients with chronic obstructive pulmonary disease (COPD) to respiratory infections, which are common causes of acute exacerbations of COPD (AECOPD). To understand the underlying mechanisms, we assessed regulatory T (Treg) cells and the expression of an inhibitory T‐cell receptor, cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4). Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with AECOPD (n = 17), patients with stable COPD (sCOPD; n = 24) and age‐matched healthy non‐smoking controls (n = 26) were cultured for 24 hr with brefeldin‐A or monensin to detect intracellular or surface CTLA‐4 (respectively) by flow cytometry. T cells in PBMC from AECOPD (n = 9), sCOPD (n = 14) and controls (n = 12) were stimulated with anti‐CD3 with and without anti‐CTLA‐4 blocking antibodies and cytokines were quantified by ELISA. Frequencies of circulating T cells expressing intracellular CTLA‐4 were higher in sCOPD (P = 0·01), whereas patients with AECOPD had more T cells expressing surface CTLA‐4 than healthy controls (P = 0·03). Increased frequencies of surface CTLA‐4⁺ CD4⁺ T cells and CTLA‐4⁺ Treg cells paralleled increases in plasma soluble tumour necrosis factor receptor‐1 levels (r = 0·32, P = 0·01 and r = 0·29, P = 0·02, respectively) in all subjects. Interferon‐γ responses to anti‐CD3 stimulation were inversely proportional to frequencies of CD4⁺ T cells expressing intracellular CTLA‐4 (r = −0·43, P = 0·01). Moreover, CTLA‐4 blockade increased the induction of interferon‐γ, tumour necrosis factor‐α and interleukin‐6 in PBMC stimulated with anti‐CD3. Overall, chronic inflammation may expand sub‐populations of T cells expressing CTLA‐4 in COPD patients and therefore impair T‐cell function. CTLA‐4 blockade may restore Th1 function in patients with COPD and so aid the clearance of bacterial pathogens responsible for AECOPD.     

Characteristics of circulating monocytes at baseline and after activation in patients with intracranial aneurysm

Intracranial aneurysm (IA) is a bulging of blood vessels around the brain that is often asymptomatic but may cause severe complications and death if ruptured. Macrophage-mediated immune responses can contribute to the development of IA. During homeostasis and inflammation, circulating monocytes can infiltrate the vasculature, where they develop into macrophages, and modulate immune responses. Based on the expression of CD14 and CD16, total circulating monocytes can be distinguished into three main subsets, including the CD14⁺CD16⁻ classical monocytes, the CD14⁺CD16⁺ intermediate monocytes, and the CD14^loCD16⁺⁺ non-classical monocytes. In this study, we found that frequencies of CD14⁺CD16⁻ classical monocytes were significantly lower in IA patients than in healthy controls, while the frequencies of CD14⁺CD16⁺ intermediate monocytes and CD14^loCD16⁺⁺ non-classical monocytes were significantly higher in IA patients than in healthy controls. The frequencies of CD14⁺CD16⁺ intermediate monocytes were further elevated in IA-ruptured patients compared to those in IA-unruptured patients. Compared to classical monocytes, intermediate monocytes and non-classical monocytes presented higher TNF-α and IL-1β expression. When cocultured with autologous naive CD4 T cells, intermediate and non-classical monocytes preferentially promoted the expression of TBX21 and RORC over the expression of FOXP3 in CD4 T cells. Inhibition of TNF-α and IL-1β slightly reduced TBX21 expression and markedly reduced RORC expression, and at the same time significantly increased FOXP3 expression in CD4 T cells. Overall, this study demonstrated that the monocytes were dysregulated in IA patients in a manner that favored the development of proinflammatory responses.     

MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases

Th17 cells are a subset of CD4⁺ T cells characterized by production of IL-17 and are known to be key participants in inflammatory reactions and various autoimmune diseases. In this study we found that a subset of human CD4⁺ T cells expressing MCAM (CD146) have higher mRNA levels of RORC2, IL-23R, IL-26, IL-22, IL-17A, but not IFN-γ, compared to CD4⁺ T cell not expressing CD146. Upon TCR stimulation with CD3/CD28, CD4⁺CD146⁺ T cells secrete significantly more IL-17A, IL-6, and IL-8 than do CD4⁺CD146⁻ T cells. Low frequencies of CD4⁺CD146⁺ T cells are found in the circulation of healthy adults, but the frequency of these cells is significantly increased in the circulation of patients with inflammatory autoimmune diseases including Behcet’s, sarcoidosis and Crohn’s disease. Patterns of gene expression and cytokine secretion in these cells are similar in healthy and disease groups. In Crohn’s disease, the increase in CD4⁺CD146⁺ cells in the circulation correlates with disease severity scores. These data indicate that expression of CD146 on CD4⁺ T cells identifies a population of committed human Th17 cells. It is likely the expression of CD146, an endothelial adhesion molecule, facilitates adherence and migration of Th17 cells through the endothelium to sites of inflammation.     

Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4 T cells of psoriasis vulgaris

Psoriasis vulgaris (PV) is a chronic inflammatory and T cell-mediated autoimmune skin disease. An immune dysfunction that is manifested by abnormally activated T cells and defective regulatory T (Treg) cells may play an important role in the pathogenesis of PV. However, the precise mechanism of the immune dysfunction in PV patients still remains unclear. In this study, we found that miR-210 expression is increased significantly in CD4⁺ T cells from patients with PV and confirmed that FOXP3 is a target gene of miR-210. We also found that overexpression of miR-210 inhibits FOXP3 expression and impairs the immunosuppressive functions of Treg cells in CD4⁺ T cells from healthy controls. In contrast, inhibition of miR-210 increases FOXP3 expression and reverses the immune dysfunction in CD4⁺ T cells from patients with PV. Our data demonstrates that increased miR-210 induces immune dysfunction via by FOXP3 in CD4⁺ T cells from patients with PV.     

Thyroid cancer metastasis is associated with an overabundance of defective follicular helper T cells

Metastatic thyroid cancers are more difficult to treat and have a significantly worse prognosis than localized thyroid cancers. Previous studies have shown that follicular helper T cells (Tfh) may participate in antitumor immune responses. Here, we investigated the characteristics of Tfh cells in patients with differentiated thyroid cancer (DTC) at various severities, including patients with localized disease, cervical metastasis, and distant metastasis. In circulating CD4 T cells, the proportion of CD4⁺CXCR5⁺ Tfh-like cells was significantly higher in patients with distant metastasis than in healthy controls, patients with local disease, and patients with cervical metastasis. Also, the expression of Tfh cell-associated surface molecules, such as PD-1, ICOS, and BTLA, tended to be higher in patients with cervical and distant metastasis than in healthy controls. However, the expression of secreted molecules, such as IL-10, IL-21, and CXCL13, was significantly lower in patients with distant metastasis than in healthy controls and patients with local disease. Additionally, circulating Tfh-like cells from patients with distant metastasis were less capable of supporting B-cell growth and IgM secretion. We also examined the CD4⁺CXCR5⁺ Tfh-like cells in tumor samples. Tumor-infiltrating Tfh-like cells were highly enriched in the pulmonary metastasis compared to the local tumor and the cervical metastasis. However, tumor-infiltrating Tfh-like cells from pulmonary metastasis displayed higher PD-1, TIM-3, and lower IL-21 expression than those from the local tumor. Together, this study identified that the metastasis of DTC patients was associated with an overabundance of defective Tfh cells.     

Localization of IL-17+Foxp3+ T Cells in Esophageal Cancer

The etiology of cancer is unclear. Recent studies indicate that some cytokines, such as interleukin (IL)-17, and regulatory T cells are involved in the development of cancer. This study aims to detect a subset of T cell, IL17+Foxp3+ T cell, in the pathogenesis of esophageal cancer (Eca). Twelve patients with squamous Eca were recruited in this study. The surgically removed Eca tissue was collected. Cells isolated from Eca tissue were analyzed by flow cytometry. The results showed that 2–10% Eca tissue-derived CD4⁺ T cells expressed Foxp3; only 0.2–0.8% non-ca tissue-derived CD4⁺ T cells expressed Foxp3. Further analysis showed that 3–15% Eca-isolated CD4⁺ T cells were also IL-17 positive whereas only 0.4–1.5% non-ca tissue-isolated CD4⁺ T cells were IL-17 positive. We also found that about 4.8–11.2% Foxp3⁺ IL-17⁺ T cells in isolated CD4⁺ T cells from Eca tissue that were significantly less than in non-ca tissue derived CD4⁺ T cells. Less than 1% Foxp3⁺ IL-17⁺ T cells in isolated CD4⁺ T cells in both Eca patients and healthy controls. Treatment with hypoxia markedly increased the expression of IL-6 in peripheral CD68+ cells. Coculturing CD68+ cells and Foxp3+ T cells under hypoxic environment resulted in abundant expression of IL-17 in Foxp3+ T cells that could be blocked by pretreatment with either anti-IL-17 or anti-transforming growth factor beta antibodies. We conclude that IL-17+Foxp3+ T cells may contribute to the development of Eca.     

Aging and human CD4 regulatory T cells

Alterations in immunity that occur with aging likely contribute to the development of infection, malignancy and inflammatory diseases. Naturally occurring CD4⁺ regulatory T cells (Treg) expressing high levels of CD25 and forkhead box P3 (FOXP3) are essential for regulating immune responses. Here we investigated the effect of aging on the number, phenotypes and function of CD4⁺ Treg in humans. The frequency and phenotypic characteristics of CD4⁺, FOXP3⁺ T cells as well as their capacity to suppress inflammatory cytokine production and proliferation of CD4⁺, CD25⁻ T cells (target cells) were comparable in young (age ≤40) and elderly (age ≥65) individuals. However, when CD4⁺, FOXP3⁺ Treg and CD4⁺, CD25⁻ T cells were co-cultured at a ratio of 1:1, the production of anti-inflammatory cytokine IL-10 from CD4⁺, CD25⁻ T cells was more potently suppressed in the elderly than in the young. This finding was not due to changes in CTLA-4 expression or apoptosis of CD4⁺, FOXP3⁺ Treg and CD4⁺, CD25⁻ T cells. Taken together, our observations suggest that aging may affect the capacity of CD4⁺, FOXP3⁺ T cells in regulating IL-10 production from target CD4⁺ T cells in humans although their other cellular characteristics remain unchanged.     

Increased frequency and FOXP3 expression of human CD8+CD25High+ T lymphocytes and its relation to CD4 regulatory T cells in patients with hepatocellular carcinoma

The mechanism of action of CD8⁺CD25^High+FOXP3⁺ T cells in hepatocellular carcinoma (HCC) has not been fully understood. Herein, the role of CD8⁺CD25^High+FOXP3⁺ T cells in HCC was compared with that of CD4⁺CD25^High+FOXP3⁺ regulatory T cells (conventional Tregs). Thirty-five patients with HCC and twenty age and sex-matched healthy adults (controls) were enrolled. The percentage of CD8⁺CD25^High+FOXP3⁺ T cells and conventional Tregs in peripheral blood was measured by flow cytometry. Our results revealed that the percentage of peripheral CD8⁺CD25^High+FOXP3⁺ T cells in HCC patients was significantly higher than controls (P = 0.005). The conventional Tregs showed the same trend with a higher level in HCC than controls (P < 0.0001). FOXP3 expression of CD8⁺CD25^High+ T cells is higher than that of CD8⁺CD25^low+ and CD8⁺CD25^Negative T cells. The percentage of CD8⁺CD25^High+FOXP3⁺ T cells positively correlated with that of conventional Tregs in HCC patients but not in controls. The higher alpha-fetoprotein positively correlated with the higher CD8⁺CD25^High+FOXP3⁺ T cells and conventional Tregs (R2 = 0.481, P < 0.0001 and R2 = 0.249, P = 0.001, respectively). The frequency of both CD8⁺CD25^High+FOXP3⁺ T cells and conventional Tregs was significantly increased in HCC with multiple lesions compared with those with one or two lesions. In conclusion: CD8⁺CD25^High+FOXP3⁺ T cells similar to conventional Tregs might be used as biomarkers of HCC progression. Therapy targeting the peripherally expanded CD8⁺CD25^High+FOXP3⁺ T cells may provide a novel perspective for HCC treatment.     

Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

An important aspect of clinical immunity to malaria is the ability to down‐regulate inflammatory responses, once parasitaemia is under control, in order to avoid immune‐mediated pathology. The role of classical (CD4⁺CD25⁺CD127^lo/?FOXP3⁺) Treg in this process, however, remains controversial. Thus, we have characterized the frequency, phenotype and function of Treg populations, over time, in healthy individuals in The Gambia. We observed that both the percentage and the absolute number of CD4⁺FOXP3⁺CD127^lo/? T cells were higher among individuals living in a rural village with highly seasonal malaria transmission than among individuals living in an urban area where malaria rarely occurs. These CD4⁺FOXP3⁺CD127^lo/? T cells exhibited an effector memory and apoptosis‐prone phenotype and suppressed cytokine production in response to malaria antigen. Cells from individuals exposed to malaria expressed significantly higher levels of mRNA for forkhead box P3 and T‐box 21 (T‐BET) at the end of the malaria transmission season than at the end of the non‐transmission season. Importantly, the ratio of T‐BET to forkhead box P3 was remarkably consistent between populations and over time, indicating that in healthy individuals, a transient increase in Th1 responses during the malaria transmission season is balanced by a commensurate Treg response, ensuring that immune homeostasis is maintained.     

CD4 T Cell Clones Producing both Interferon-γ and Interleukin-10 Predominate in Bronchoalveolar Lavages of Active Pulmonary Tuberculosis Patients

The pattern of cytokine production in T cell clones derived from bronchoalveolar lavages (BAL) of active pulmonary tuberculosis (TB) patients was analyzed in clones obtained by limiting dilution procedures which expand with high efficiency either total T lymphocytes, independently of their antigen-recognition specificity, or Mycobacterium tuberculosis-specific T cells. BAL-derived clones, representative of CD4⁺ cells from five patients with active TB, produced significantly higher amounts of IFN-γ than BAL-derived CD4⁺ clones from three inactive TB donors or four controls (with unrelated, noninfectious pathology). Average IL-4 and IL-10 production did not differ significantly in the three groups. Although these data suggest a predominant Th1 response to M. tuberculosis infection in the lungs, the majority of BAL-derived CD4⁺ clones produced both IFN-γ and IL-10 and the percentage of clones with this pattern of cytokine production was significantly higher in clones derived from BAL of active TB patients than from controls. Only rare clones derived from peripheral blood (PB)-derived CD45RO⁺ CD4⁺ T cells of both patients (nine cases) and controls (four cases) produced both IFN-γ and IL-10; instead, the IL-10-producing clones derived from PB T cells most often also produced IL-4, displaying a typical Th2 phenotype. Higher average amounts of IFN-γ and IL-10 were produced by BAL-derived CD8⁺ clones of four active TB patients than of four controls, although the frequency of CD8⁺ clones producing both IFN-γ and IL-10 was lower than that of CD4⁺ clones. The M. tuberculosis-specific BAL-derived T cell clones from three active TB patients were almost exclusively CD4⁺ and produced consistently high levels of IFN-γ often in association with IL-10, but very rarely with IL-4. Unlike the BAL-derived clones, the M. tuberculosis-specific clones derived from PB CD45RO⁺ CD4⁺ T cells of three different active TB patients and two healthy donors showed large individual variability in cytokine production as well as in the proportion of CD4⁺, CD8⁺, or TCR γ/δ⁺ clones. These results indicate the predominance of CD4⁺ T cells producing both the proinflammatory cytokine IFN-γ and the anti-inflammatory cytokine IL-10 in BAL of patients with active TB.     

FOXP3 expression and frequency of regulatory T cells in healed individuals from Leishmania major infection and the asymptomatic cases

Two groups of residents in an endemic area of Leishmania major infection in Iran with positive leishmanin skin tests who were either asymptomatic or had healed cutaneous leishmaniasis lesions were compared with respect to their T helper responses. The percentages of regulatory T cells (T_reg; CD4⁺CD25^high FoxP3⁺) from the peripheral blood and CD4⁺ T cells producing intracellular cytokines (IL-4, IL-10, IL-17 and IFN-γ) from the stimulated PBMCs were evaluated by flow cytometry and the expressions of RORC and FOXP3 genes were quantified by real-time RT-PCR. T responder (CD4⁺CD25⁻) and T_reg-enriched (CD4⁺CD25⁺) cells were isolated magnetically and the suppressive capacity of the latter and the cytokines (IFN-γ, TGF-β and IL-10) secreted from them were evaluated by in vitro assays. The results showed that the frequency of T_reg in the studied groups were similar and T_reg from both groups exhibited high yet similar suppressive capacities while significantly higher levels of FOXP3 expression was observed in the asymptomatic group. Taken together, similar frequency and suppressiveness of T_reg combined with high ratios of IFN-γ/IL-10 producing CD4⁺ T cells were common in both groups; however the members of the asymptomatic group appeared to require higher expression of FOXP3 to maintain their immunity to re-infection.     

Type 2 diabetes mellitus is associated with altered CD8+ T and natural killer cell function in pulmonary tuberculosis

Type 2 diabetes mellitus (DM) is associated with expanded frequencies of mycobacterial antigen-specific CD4⁺ T helper type 1 (Th1) and Th17 cells in individuals with active pulmonary tuberculosis (TB). No data are available on the role of CD8⁺ T and natural killer (NK) cells in TB with coincident DM. To identify the role of CD8⁺ T and NK cells in pulmonary TB with diabetes, we examined mycobacteria-specific immune responses in the whole blood of individuals with TB and DM (TB-DM) and compared them with those without DM (TB-NDM). We found that TB-DM is characterized by elevated frequencies of mycobacterial antigen-stimulated CD8⁺ T cells expressing type 1 [interferon-γ and interleukin-2 (IL-2)] and type 17 (IL-17F) cytokines. We also found that TB-DM is characterized by expanded frequencies of TB antigen-stimulated NK cells expressing type 1 (tumour necrosis factor-α) and type 17 (IL-17A and IL-17F) cytokines. In contrast, CD8⁺ T cells were associated with significantly diminished expression of the cytotoxic markers perforin, granzyme B and CD107a both at baseline and following antigen or anti-CD3 stimulation, while NK cells were associated with significantly decreased antigen-stimulated expression of CD107a only. This was not associated with alterations in CD8⁺ T-cell or NK cell numbers or subset distribution. Therefore, our data suggest that pulmonary TB complicated with type 2 DM is associated with an altered repertoire of cytokine-producing and cytotoxic molecule-expressing CD8⁺ T and NK cells, possibly contributing to increased pathology.     

Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis

T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People’s Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3⁺CD4⁺IL-17⁺) and Th1 (CD3⁺CD4⁺IFN-γ⁺) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP.     

Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disorder caused by mutations in the FOXP3 gene, which plays a key role in the generation of CD4⁺CD25⁺regulatory T (Treg) cells. We selected CD127 as the surface marker of Treg cells to illustrate the development and function of Treg cells in IPEX syndrome. CD4⁺CD25⁺FOXP3⁺ T cells, the putative Treg cells, were almost completely absent in all patients. Importantly, a substantial number of CD4⁺CD25⁺CD127^low T cells were observed in 3 IPEX patients with hypomorphic mutations in the FOXP3 gene. We demonstrated that CD4⁺CD25⁺CD127^low T cells isolated from these 3 patients exhibited an appreciable suppressive activity on effector T cell proliferation, although less than that displayed by Treg cells from healthy controls. These results suggest that genetically altered FOXP3 can drive the generation of functionally immature Treg cells, but that intact FOXP3 is necessary for the complete function of Treg cells.     

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.     

Imbalance of Different Types of CD4+Foxp3+ T cells in renal transplant recipients

Aims: To determine the number of CD4⁺CD25^-Foxp3⁺, CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells in renal transplant recipients that are transplanted stable (TS), or experiencing accelerated rejection (ALR), or acute rejection (AR).

Methods: Renal transplantation was conducted in 28 patients with end-stage renal failure (ESRF). The number of peripheral CD4⁺CD25^-Foxp3⁺, CD4⁺CD25⁺Foxp3⁺, or CD4⁺CXCR5⁺Foxp3⁺ T cells and the serum levels of interleukin-10 (IL-10) were measured in pre- and post-transplant patients and these results were compared to 10 healthy controls (HC). Correlation between CD4⁺CD25⁺Foxp3⁺ and estimated glomerular filtration rate (eGFR), CD4⁺CD25^-Foxp3⁺ and serum creatinine (Cr) levels, or Cr and IL-10 levels in TS patients was also determined.

Results: The number of CD4⁺CD25^-Foxp3⁺ T cells was significantly increased in patients with ESRF, as compared to HC. Stratification analysis demonstrated that TS patients contained greater numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells, higher levels of serum IL-10, and fewer numbers of CD4⁺CD25^-Foxp3⁺ T cells than ESRF patients. In contrast, ALR and AR patients contained fewer numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CXCR5⁺Foxp3⁺ T cells, greater numbers of CD4⁺CD25^-Foxp3⁺ T cells, and lower levels of serum IL-10 than ESRF patients. In TS patients, the numbers of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^-Foxp3⁺ T cells were positively correlated with eGFR and serum Cr levels, respectively.

Conclusion: An imbalance of different types of CD4⁺Foxp3⁺ T cells might be involved in renal transplant rejection.     

Induction of contact-dependent CD8(+) regulatory T cells through stimulation with staphylococcal and streptococcal superantigens

The bacterial superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes are potent stimulators of polyclonal T-cell proliferation. They are the causes of toxic shock syndrome but also induce CD25⁺ FOXP3⁺ regulatory cells in the CD4 compartment. Several studies have recently described different forms of antigen-induced regulatory CD8⁺ T cells in the context of inflammatory diseases and chronic viral infections. In this paper we show that bacterial superantigens are potent inducers of human regulatory CD8⁺ T cells. We used four prototypic superantigens of S. aureus (toxic shock syndrome toxin-1 and staphylococcal enterotoxin A) and Str. pyogenes (streptococcal pyrogenic exotoxins A and K/L). At concentrations below 1 ng/ml each toxin triggers concentration-dependent T-cell receptor Vβ-specific expression of CD25 and FOXP3 on CD8⁺ T cells. This effect is independent of CD4⁺ T-cell help but requires antigen-presenting cells for maximum effect. The cells also express the activation/regulatory markers cytotoxic T-lymphocyte antigen-4 and glucocorticoid-induced tumour necrosis factor receptor-related protein and skin homing adhesins CD103 and cutaneous lymphocyte-associated antigen. Superantigen-induced CD25⁺ FOXP3⁺ CD8⁺ T cells were as potent as freshly prepared naturally occurring CD4⁺ regulatory T cells in suppressing proliferation of CD4⁺ CD25⁻ T cells in response to anti-CD3 stimulation. Although superantigen-induced CD8⁺ CD25⁺ FOXP3⁺ express interleukin-10 and interferon-γ their suppressive function is cell contact dependent. Our findings indicate that regulatory CD8⁺ T cells may be a feature of acute bacterial infections contributing to immune evasion by the microbe and disease pathogenesis. The presence and magnitude of regulatory CD8⁺ T-cell responses may represent a novel biomarker in such infections. Superantigen-induced regulatory CD8⁺ T cells also have therapeutic potential.