Blocking ICOS-B7h Signal Can Inhibit the Function of Allogene T Lymphocytes and Decrease the Incidence and Severity of Acute Graft Versus Host Disease in Mouse Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4606-4606
Author(s):  
Xiaochen Bao ◽  
Ningxia Song ◽  
Bin Wang ◽  
Jianmin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Recipient Mouse ◽  
T Helper ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract ICOS, a CD28 family member expressed on activated T cells, plays important roles in T cell activation and effector function. Here we report our results of biological activity of ICOS signal on allogeneic T lymphocytes and its effect on acute graft-versus-host disease in mouse model by blocking ICOS-B7h signal with ICOS-Ig fusion protein. Human ICOSIg fusion protein was harvested and purified from supernatant of CHO cells transfected with pSecTag2/Hygro A-ICOS-Ig in our lab. Spleen CD4+ cells from C57BL/6 mouse were stimulated with dendritic cells from BALB/C mouse, with different doses of ICOS-Ig or human-Ig (h-Ig) as controls. Allogeneic aGVHD model was established with lethally irradiated BALB/c recipients receiving allogeneic BM and spleen T cells from C57BL/6 mouse with 100ug ICOS-Ig or h-Ig intropenetoneally 4 times at day 0, day +2, +4 and +6 of transplantation. RESULTS: ICOS-Ig (10ug/mL) significantly inhibited proliferation of CD4+T cells ( P<0.01), decreased the level of TNF-α and elevated level of IL-4 in the supernatants of CD4+ T cells in response to allogeneic mature DCs but had no effect on IFN-γ production; ICOS-Ig blockade elevated apoptosis of splenic CD4+ T cells while had no effect on T cell activation (CD25 expression). ICOS-Ig blockade significantly attenuated the lethal GVHD that occurred in control recipient mice. The average survival time was 13.25±5.87 days for mice in h-Ig group, while 21.42±3.02 days for animals in ICOS-Ig group(p=0.0217). Pathologic evaluation revealed that the liver and intestine of animals in ICOS-Ig group has less lymphocyte infiltration and less architectural disruption than those in control h-Ig group; In vivo, ICOS-Ig had no effect on allogeneic T cells division (h-Ig :98.40±1.32, ICOS-Ig: 97.69±2.19 by FACS analysis of CFSE labeled lymphocyte at day 3 of transplantation) and no effect on the proportion of CD4+/CD8+ (h-Ig: 26.35±0.07, ICOS-Ig: 22.12±0.21), but increased apoptosis of allogeneic CD8+ T cells in GVHD model by FACS analysis of Annexin-V staining lymphocytes at day 10 of transplantation (h-Ig: 20.44±3.83, ICOS-Ig: 22.87±6.94 in CD4+ T cells; h-Ig: 18.73±7.43, ICOS-Ig: 24.03±5.4 in CD8+ T cells). Spleen T cells from mice after transplantation were stimulated by ConA ex vivo, ICOS-Ig group proliferated less than control h-Ig group through cell counting with CCK-8 (h-Ig: 0.86±0.04,ICOS-Ig: 0.69±0.12,P<0.05). (4) ICOS-Ig significantly reduced the secretion of IFN-γ and elevated IL-4 in the serum of recipient mouse. The IFN-γ (pg/mL) detected were 562.27±49.97 in h-Ig group, 49.79±2.81 in ICOS-Ig group; and the IL-4 (pg/mL) detected were 38.819±27.56 in h-Ig group,456.03±69.63 in ICOS-Ig group. (p<0.05). (5)ICOS-Ig significantly reduced the secretion of T-bet and elevated GATA-3 in the spleens of recipient mouse. The T-bet/GATA-3 detected were 1.87±0.65 in h-Ig group, 0.56±0.03 in ICOS-Ig (p=0.03). CONCLUSION: The ICOS-Ig fusion protein had bioactivity of inhibition of T cell proliferation and alternated the polarization of T helper cells; It promoted the apoptosis of allo-reactive T cells from donor animals but had no effect on the activation of allo-reactive CD4+T cells; ICOS-Ig blockade can prevent aGVHD through attenuating the function of the allo-reactive T cells, elevating apoptosis of allo-reactive T cells and alternating the polarization of T helper cells.

scholarly journals Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

2020 ◽  
Author(s):  
Cheleka A.M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
Munyaradzi Musvosvi ◽  
One B Dintwe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Cd4 T Cell ◽  
Remote Infection ◽  
Ifn Γ

AbstractBackgroundRecent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection.MethodsHealthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterized M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+.FindingsCFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection.InterpretationRecent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection.

scholarly journals Gamma Interferon Responses of CD4 and CD8 T-Cell Subsets Are Quantitatively Different and Independent of Each Other during Pulmonary Mycobacterium bovis BCG Infection

2007 ◽  
Vol 75 (5) ◽  
pp. 2244-2252 ◽  
Author(s):  
Patricia Ngai ◽  
Sarah McCormick ◽  
Cherrie Small ◽  
Xizhong Zhang ◽  
Anna Zganiacz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mycobacterial Infection ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.

Paradoxical Effects of Interferon-γ in Allogeneic Bone Marrow Transplant: Donor Dendritic Cells Regulate Graft-Versus-Leukemia and Graft- Versus-Host Disease Activities.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2343-2343
Author(s):  
Ying Lu ◽  
Jian-Ming Li ◽  
Wayne Harris ◽  
Edmund Waller
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interferon Γ ◽  
Wild Type ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Both host and donor dendritic cells (DCs) have been shown to play a critical role in regulating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after MHC-mismatched bone marrow transplantation (BMT) (Shlomchik et al. Science 1999, Reddy et al. Nat Med 2005). In contrast to host DCs, much less is known about the precise mechanisms donor DCs may use to modulate donor T-cell activation and GVL activity. A clinical report has suggested an association between the number of donor plasmacytoid DC in the graft and leukemia relapses after allogeneic BMT (Waller et al. Blood 2001). Using allogeneic MHC-mismatched hematopoietic stem cell transplant (HSCT) (C57BL/6→B10.BR) in mice bearing the T lymphoblastic leukemia LBRM, we have previously reported that recipients transplanted with purified CD11b− DC in combination with purified HSC and T-cells had 45% increased long-term leukemia-free-survival, higher numbers of interferon-γ (IFN-γ) producing donor T-cells as well as higher levels of serum IFN-γ (Li et al. Blood 2007). The aim of the present work is to further define whether production of IFN-γ by donor T-cells is necessary for the augmentation of GVL effect seen with CD11b− donor DC and define the mechanism that donor CD11b− DC can augment GVL of donor T-cells without causing fatal GVHD. To evaluate the role for IFN-γ produced by donor T-cells, we used IFN-γ knockout (KO) mice as donors in the C57BL/6→B10.BR transplant model. Recipients of IFN-γ KO donor T-cells in combination with wild-type FACS-purified HSC and CD11b− DC died rapidly with 0% survival at day 80 compared with 65% survival among tumor-bearing recipients of donor CD11b− with wild-type HSC and T-cells and 75% survival in mice transplanted with wild-type cells in the absence of LBRM. Moreover, the addition of donor CD11b− DC to IFN-γ KO donor T-cells did not lead to further augmentation of GVHD. These data supported a role for donor T-cell-derived IFN-γ in the enhanced GVL activity seen among recipients of donor CD11b− DC,but did not explain the lack of increased GVHD. As a potent pro-inflammatory cytokine initiating immune response in GVHD, IFN-γ has also been demonstrated to show a suppressive effect during GVHD as a result of IFN-γ-inducible indoleamine-2,3-dioxygenase(IDO) gene expression. CD11b− DCs were freshly isolated from bone marrow of donor C57BL/6 mice, exposed to 100ng/ml IFN-γ for 18 hours, and the IDO expression was measured by intracellular staining. The results showed that following IFN-γ treatment, IDO levels of CD11b− DCs were up-regulated. Furthermore, in vitro co-culture of FACS-purified CD11b− DC with syngeneic T-cells in the presence of allogeneic antigen also demonstrated increased IDO levels on the co-cultured DCs. Taken together, our data support a model in which donor CD11b− DCs initially induce Th1 polarization of activated donor T-cells that secret high levels of IFN-γ in the lymph node microenvironment. High local levels of IFN-γ subsequently induce IDO expression in DC, resulting in down-modulation of T-cell allo-reactivity and GVHD. Thus, IFN-γ-induced IDO expression on CD11b− donor DCs appears to be a critical downstream event that inhibits continued T-cell activation and leads to less severe GVHD.

scholarly journals 2406 The microbial-derived short-chain fatty acid butyrate directly and differentially inhibits gut T helper cell subset activation and proliferation

2018 ◽  
Vol 2 (S1) ◽  
pp. 31-32
Author(s):  
Jon Kibbie ◽  
Stephanie Dillon ◽  
Moriah Castleman ◽  
Jay Liu ◽  
Martin McCarter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
T Helper ◽  
T Helper Subsets ◽  
Hiv 1

OBJECTIVES/SPECIFIC AIMS: A hallmark of progressive HIV-1 infection is the massive activation and depletion of the gut barrier protective CD4 T helper subsets (Th17 and Th22) in the intestinal mucosa. The loss of these cells is thought to contribute to microbial translocation and systemic immune activation that occurs during chronic infection. In addition to the loss of protective Th subsets, we previously showed that chronically HIV-1 infected individuals have an altered colonic mucosal microbiome, which is in part characterized by a lower relative abundance of bacteria that produce the short-chain fatty acid butyrate in conjunction with increased relative abundance of gram-negative pathobionts. This dysbiosis was linked to markers of mucosal and systemic immune activation in these individuals. Following up on these clinical observations, we sought to understand how a loss of butyrate might contribute to HIV-associated inflammation. Initial studies showed that the addition of butyrate to cultured lamina propria mononuclear cells (LPMC) resulted in decreased pathobiont-driven gut T cell activation, HIV-1 infection levels and production of IL-17 and IFNy. Since the gut barrier protective Th17 and Th22 subsets are preferentially infected and depleted, which is critical to HIV-1 pathogenesis, we wanted to determine the mechanism by which butyrate modulates activation of these important Th subsets in the gut. METHODS/STUDY POPULATION: Total LPMCs or purified LP CD4 T cells were isolated from human jejunal tissue (n=3–6), labeled with CFSE and cultured with TCR/CD28 beads to mimic APC driven T cell activation, with the addition of butyrate at physiologic doses(0–2 mM). Four days after culture, secreted cytokine(IL-17 and IFNy) levels were measured by ELISA. Cells were then short-term (4 hr) mitogenically stimulated (PMA/Ionomycin) in the presence of a golgi transport inhibitor. Total CD4 T cell activation (CD38+/HLA-DR+, CD25+), proliferation (CFSElow), and frequencies of intracellular cytokines were measured by multi-color flow cytometry. Paired t-tests were performed to determine statistical significance. RESULTS/ANTICIPATED RESULTS: Butyrate inhibited LP CD4 T cell activation (p=0.013) and proliferation (p=0.015) within total LPMCs stimulated with TCR/CD28 beads in a dose-dependent manner, with significant activity starting at 0.125 mM. Quantification of total secreted cytokines revealed that butyrate significantly decreased both IL-17 and IFNy production after 4 days of culture at 0.0625 mM and 0.25 mM of butyrate, respectively. Assays using purified LP CD4 T cells demonstrated that butyrate directly decreased LP CD4 T cell activation, proliferation and cytokine production in response to TCR/CD28 stimulation. Studies on specific T helper subsets revealed that butyrate inhibited proliferation of Th17 cells at lower concentrations (IC50:0.147 mM) compared with Th1 (IC50:0.229 mM) and Th22 (IC50:0.258 mM) and Th non-IL-22/IL-17/IFNy producing (IC50:2.14 mM) subsets. In addition, it appeared there was a paradoxical increase of HIV-1 infection levels at lower concentrations of butyrate (0.125 mM). DISCUSSION/SIGNIFICANCE OF IMPACT: The addition of butyrate to activated LP CD4 T cells decreases TCR-mediated activation in a dose-dependent manner, and butyrate acts directly on purified LP CD4 T cell populations independent of other cell populations. Butyrate differentially inhibited the proliferation of Th17, Th1, and Th22 subsets, with Th17 cells being the most sensitive to butyrate but increased the infection levels of all T helper subsets at low concentrations. Further studies are needed to determine the mechanism of butyrate’s actions on LP Th cells and the sensitivity of Th17 cells to the inhibitory effects of butyrate. These results could help direct targeted manipulation of the colonic microbiome of HIV-1 infected individuals to help resolve inflammation and limit the impact of the infection in the gut mucosa and systemically.

CD26 Blockade by Humanized Monoclonal Antibody Leads to Prophylaxis and Treatment of Graft-Versus-Host Disease (GVHD) in Hu-PBL-NOG Model Mice,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4018-4018
Author(s):  
Ryo Hatano ◽  
Kei Ohnuma ◽  
Taketo Yamada ◽  
Takaaki Ooki ◽  
Junpei Yamamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Human Lymphocytes ◽  
Graft Versus Host ◽  
Human T Cells

Abstract Abstract 4018 CD26 is a 110-kDa multifunctional membrane-bound glycoprotein with dipeptidyl peptidase IV (DPPIV) enzyme activity present on a wide variety of cells, and is critical in T cell biology, as a marker of T cell activation. The role of CD26 in immune regulation has been extensively characterized, with our recent findings elucidating its linkage with signaling pathways and structures involved in T cell activation as well as antigen presenting cell (APC)-T cell interaction. CD26 in human T cells has a costimulatory function and is upregulated after activation. On the other hand, in murine lymphocytes, CD26 is expressed in CD4-CD8- thymocytes and its expression level is not changed by various stimulation procedures. Moreover, murine T cells are not observed to be activated via CD26. Therefore, for the analysis of CD26-mediated immuneregulation leading to clinical applications, it is necessary to use a pathological model system caused by human T cells but not murine T cells. For this purpose, we used a xenogeneic graft-versus-host disease (x-GVHD) murine model, which is generated by transplantation of human T cells into NOG-Scid mice (hu-PBL-NOG). In this model mouse, x-GVHD is developed by manifesting rough hair, loss of weight and motility, since transplanted human T cells become effector cells in murine organs. By examining the cytotoxic functions of human CD8+ T cells after CD26-mediated costimulation in vitro, we have shown that CD26-mediated costimulation induced vigorous secretion of inflammatory cytokines, TNF-a, IFN-g and soluble Fas Ligand, and strongly enhanced the expression of Granzyme B. These results suggested that cytotoxic function in human CD8+ T cells activated via CD26-mediated costimulation has a key role in developing x-GVHD. In the present study, we showed that CD26 blockade by humanized anti-CD26 monoclonal antibody (huCD26mAb) reduced development of x-GVHD, and that this effect of CD26 blockade was exerted by suppression of cytotoxic activity of human CD8+ T cells in vivo. Moreover, huCD26mAb showed as same effect on suppression of x-GVHD as clinically available drug, abatacept (CTLA4-Ig), a blockade of CD28-mediated costimulation. While increased dose of CTLA4-Ig showed more suppressive effect on x-GVHD but sustained suppression of engraftment of transplanted human T cells, the same dose of huCD26mAb showed no delay in engraftment. We performed a further analysis of peripheral human lymphocytes in hu-PBL-NOG after administration of huCD26mAb or CTLA4-Ig. Although CD26 expression on both human CD4+ T cells and CD8+ T cells was markedly increased in control mice with human IgG administration as compared with those before transplantation, the engraftment of human CD26+ T cells was completely inhibited in huCD26mAb administered hu-PBL-NOG. As a result of analysis of human T cells engrafted in spleen of NOG-Scid mice transplanted with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled human lymphocytes, huCD26mAb administration preferentially suppressed the priming of human CD8+ T cells rather than CD4+ T cells, while CTLA4-Ig strongly suppressed the cell division of both human CD4+ T cells and CD8+ T cells. Our data strongly suggested that CD26-mediated costimulatory activation in human CD8+ T cells was deeply involved in the pathogenesis of x-GVHD, and blocking the CD26-mediated costimulation resulted in prophylaxis and treatment of x-GVHD. Taken together, our results support the notion that CD26 blockade by huCD26mAb may become a promising therapeutic strategy for GVHD and other refractory immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-γ

2007 ◽  
Vol 292 (6) ◽  
pp. G1630-G1640 ◽  
Author(s):  
Iris Dotan ◽  
Matthieu Allez ◽  
Atsushi Nakazawa ◽  
Jens Brimnes ◽  
Micoll Schulder-Katz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel ◽  
Ifn Γ

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-γ, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-γ indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

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