Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic cells
Tithi GhoshSubhasis BarikAvishek BhuniyaJesmita DharShayani DasguptaSarbari GhoshMadhurima SarkarIpsita GuhaKoustav SarkarPinak ChakrabartiBhaskar SahaWalter J. StorkusRathindranath BaralAnamika Bose
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Abstract:
Mesenchymal stem cells (MSCs) represent an important cellular constituent of the tumor microenvironment, which along with tumor cells themselves, serve to regulate protective immune responses in support of progressive disease. We report that tumor MSCs prevent the ability of dendritic cells (DC) to promote naïve CD4 + and CD8 + T cell expansion, interferon gamma secretion and cytotoxicity against tumor cells, which are critical to immune‐mediated tumor eradication. Notably, tumor MSCs fail to prevent DC‐mediated early T cell activation events or the ability of responder T cells to produce IL‐2. The immunoregulatory activity of tumor MSCs is IL‐10‐ and STAT3‐dependent, with STAT3 repressing DC expression of cystathionase, a critical enzyme that converts methionine‐to‐cysteine. Under cysteine‐deficient priming conditions, naïve T cells exhibit defective cellular metabolism and proliferation. Bioinformatics analyses as well as in vitro observations suggest that STAT3 may directly bind to a GAS‐like motif within the cystathionase promoter (−269 to −261) leading to IL‐10‐STAT3 mediated repression of cystathionase gene transcription. Our collective results provide evidence for a novel mechanism of tumor MSC‐mediated T cell inhibition within tumor microenvironment.Background: Wound healing problems can arise in donor wounds after harvesting a full-thickness graft.Returning Mesenchymal Stem Cells (MSCs) on the wounds may accelerate wound healing.The aim of this study is to analyse the effect of MSCs in the epithelialization process and collagen density on full-thickness wound healing. Methods:The pilot study included 10 patients undergoing excision of a full-thickness skin graft on the groin.Patients were randomly divided into two groups: Mesenchymal Stem Cells (MSCs) and Non-Mesenchymal Stem Cells (Non-MSCs).The MSCs group had previously undergone fat harvesting which was processed into mesenchymal stem cells.Biopsies were taken from both groups on days 14 (proliferative phase) and 45 (maturation phase), and were compared with normal skin (NS; n=5).Epithelial layers of the epidermis were assessed with hematoxylin eosin staining.Collagen density was evaluated with MT staining, and analysed using a light microscope. Result:In the MSCs group and the Non-MSCs group, the number of epithelial layers were significantly higher compared to the NS-group on day 45 (14.7 ± 0.70 and 8.24 ± 0.76 vs 5.43 ± 0.60 respectively; p<0.001 and p<0.001).The collagen density in the MSCs group on day 14 was 33.3 ± 2.46% in the MSCs group and 45.7 ± 5.84% in the non-MSCs group, compared to 54.3 ± 3.71% in the NS-group (p<0.001 and p=0.012 resp.).These values increased on day 45 to 49.2 ± 3.28% in the MSCs group, and 73.4 ± 1.63% in the non-MSCs group. Conclusion:Mesenchymal stem cells increased the number of epithelial layers in the full-thickness wound healing process compared to normal skin.A higher increase was seen in the MSCs-group.On day 45, an increase in collagen density was observed in the MSCs group and Non-MSCs group.Adipose-derived mesenchymal stem cells can be used in the process of full-thickness wound healing.Future randomized controlled trials are needed to confirm these findings.
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Abstract The main conclusion from these experiments is that the antigen‐specific suppressor T cell of mice which inhibits the induction of cytotoxic T lymphocytes is not itself a cytotoxic T cell. This conclusion is supported by two main observations: first, a certain cell number from first‐step cultures which was suppressive in the presence of a high dose of antigen actually helped the cytotoxic response at a lower antigen dose. This observation is difficult to reconcile with the hypothesis that suppression is due to the killing of the stimulator or the responder cells in the second‐step culture by cytotoxic T cells. Second, cells from first‐step cultures of cortisone‐treated mice displayed cytotoxic activity but had no suppressive effect on the generation of killer cells. It was further demonstrated that these cells failed to influence in any way the suppressive effect, however weak, of cells from first‐step cultures of normal spleen. We therefore favor the view that the suppression observed in this system is due to a regulatory signal which occurs as a result of the ability of both inhibitory cells and responder cells to recognize and respond to allogeneic determinants expressed on the surface of stimulator cells. The suppressor T cells described here act by linked associative recognition of antigen. That is, suppressor T cells only inhibit the induction of a precursor cytotoxic T cell in the presence of an antigen to which both the precursor cell and the suppressor cell can bind. In this sense, suppressors act in a manner analogous to helper T cells in T‐B cell cooperation; carrier‐specific helper T cells only enhance an anti‐hapten B cell response in the presence of hapten‐carrier conjugates. Similarly, alloantigen a (carrier)‐specific suppressor T cells only inhibit alloantigen b (hapten)‐specific cytotoxic responses in the presence of (a × b)F 1 stimulator cells (hapten‐carrier conjugate), not in the presence of a mixture of parental stimulator cells (a + b).
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Sir: A number of investigators have recently reported that cell membranes, or solubilized proteins derived from them, are capable of inducing cytotoxic responses in secondary cultures (1–6). They have implied thereby that they are gaining insight into the specificity of the structures recognized by cytotoxic T cells. An alternative interpretation seems equally plausible: that the membrane preparations act not directly on cytotoxic memory cells, but rather on helper T cells, which, by secreting soluble mediators, “trigger” cytotoxic cell differentiation. This interpretation is supported by several recent reports. Thus, Ryser et al. (7), Wagner and Rollinghoff (8), and this laboratory (Okada et al. , in press) have shown that cell mediators secreted by primed Lyt I+ T cells can cause the direct differentiation of cytotoxic T cells in secondary (memory) cultures. Moreover, the specificity of the cytotoxic cells induced by these mediators is that of the antigen initially used for priming.
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Objective To compare the efficacy of intracavernosal injection of autologous and allogeneic mesenchymal stem cells as potential treatment of erectile dysfunction in an experimental rat model. Methods Mesenchymal stem cells were isolated from rat paratesticular fat tissue. Bilateral cavernous nerve injury was carried out followed by immediate intracavernosal injection of either autologous or allogeneic mesenchymal stem cells or mesenchymal stem cell lysates. One month after injection, erectile function was evaluated by means of intracavernosal pressure measurement. All rats were eventually killed, and penile tissues were taken for immunhistochemical and molecular investigation. Results A total of 36 S prague– D awley rats were used. The mean maximum intracavernosal pressure in the sham‐operated, autologous and allogeneic mesenchymal stem cell injection groups were significantly better compared with the vehicle injection group (80.5 [3.56], 71.1 [2.9] and 69.2 [3.2] vs 40.33 [4.4], respectively). Mean maximum intracavernosal pressure to mean arterial pressure ratios in the autologous and allogeneic mesenchymal stem cell and mesenchymal stem cell lysate injection groups were not significantly different. Conclusions Intracavernosal injection of both autologous or allogeneic mesenchymal stem cells improve erectile functions in a rat model of cavernous nerve injury. Allogeneic mesenchymal stem cells might provide clinicians with ready to use, standardized and, in certain cases, more effective products. More studies focusing on long‐term immunological aspects of allogeneic mesenchymal stem cells are required.
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Intracavernous injection
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Abstract Sir: A number of investigators have recently reported that cell membranes, or solubilized proteins derived from them, are capable of inducing cytotoxic responses in secondary cultures (1–6). They have implied thereby that they are gaining insight into the specificity of the structures recognized by cytotoxic T cells. An alternative interpretation seems equally plausible: that the membrane preparations act not directly on cytotoxic memory cells, but rather on helper T cells, which, by secreting soluble mediators, “trigger” cytotoxic cell differentiation. This interpretation is supported by several recent reports. Thus, Ryser et al. (7), Wagner and Rollinghoff (8), and this laboratory (Okada et al., in press) have shown that cell mediators secreted by primed Lyt I+ T cells can cause the direct differentiation of cytotoxic T cells in secondary (memory) cultures. Moreover, the specificity of the cytotoxic cells induced by these mediators is that of the antigen initially used for priming.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.
Granzyme
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