scholarly journals MHC control of CD4+ T cell subset activation.

1989 ◽  
Vol 170 (6) ◽  
pp. 2135-2140 ◽  
Author(s):  
J S Murray ◽  
J Madri ◽  
J Tite ◽  
S R Carding ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Selective Activation ◽  
Ifn Gamma

The present results demonstrate that CD4+ T cells activated in the primary in vivo response to antigen produce distinct patterns of cytokines depending upon the MHC class II haplotype of the responding mice. I-As mice were found to selectively activate IL-2/IFN-gamma-producing CD4+ T cells, whereas I-Ab mice exhibited selective activation of IL-4-producing CD4+ T cells in response to collagen IV. The effector response phenotype was found to correlate with the cytokine phenotype of CD4+ T cells activated in vivo; IL-2/IFN-gamma-producing cells giving rise to proliferative (cell-mediated) responses, IL-4-producing cells leading to secondary IgG (humoral) responses. Together the data support the notion that the outcome of a given immune response (e.g., protection vs. onset, tolerance vs. autoimmunity) may be determined in part by the type of CD4+ T cells initially activated by antigen. Moreover, the present experiments demonstrate for the first time that polymorphism in class II MHC can determine such selective activation of different cytokine-producing CD4+ T cell phenotypes.

scholarly journals Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL

2005 ◽  
Vol 202 (8) ◽  
pp. 1109-1119 ◽  
Author(s):  
Nagendra R. Hegde ◽  
Claire Dunn ◽  
David M. Lewinsohn ◽  
Michael A. Jarvis ◽  
Jay A. Nelson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Glial Cells ◽  
Human Cytomegalovirus ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Host Cells ◽  
Cd4 T Cell

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB—expressed by adenovirus vectors or after HCMV infection—and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells.

scholarly journals Deciphering the Plasmodium falciparum malaria-specific CD4+ T cell response: ex vivo detection of high frequencies of PD-1+TIGIT+ EXP1-specific CD4+ T cells using a novel HLA-DR11-restricted MHC class II tetramer

2021 ◽  
Author(s):  
Sophia Schulte ◽  
Janna Heide ◽  
Christin Ackermann ◽  
Sven Peine ◽  
Michael Ramharter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Class Ii ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Inhibitory Receptors

Abstract Relatively little is known about the ex vivo frequency and phenotype of the P. falciparum-specific CD4+ T cell response in humans. The exported protein 1 (EXP1) is expressed by plasmodia at both, the liver stage and blood stage, of infection making it a potential target for CD4+ and CD8+ effector T cells. Here, a fluorochrome-labelled HLA-DRB1*11:01-restriced MHC class II tetramer derived from the P. falciparum EXP1 (aa62-74) was established for ex vivo tetramer analysis and magnetic bead enrichment in ten patients with acute malaria. EXP1-specific CD4+ T cells were detectable in nine out of ten (90%) malaria patients expressing the HLA-DRB1*11 molecule with an average ex vivo frequency of 0.11% (0-0.22%) of total CD4+ T cells. The phenotype of EXP1-specific CD4+ T cells was further assessed using co-staining with activation (CD38, HLA-DR, CD26), differentiation (CD45RO, CCR7, KLRG1, CD127), senescence (CD57) and co-inhibitory (PD-1, TIGIT, LAG-3, TIM-3) markers as well as the ectonucleotidases CD39 and CD73. EXP1-specific tetramer+ CD4+ T cells had a distinct phenotype compared to bulk CD4+ T cells and displayed a highly activated effector memory phenotype with elevated levels of co-inhibitory receptors and activation markers: EXP1-specific CD4+ T cells universally expressed the co-inhibitory receptors PD-1 and TIGIT as well as the activation marker CD38 and showed elevated frequencies of CD39. These results demonstrate that MHC class II tetramer enrichment is a sensitive approach to investigate ex vivo antigen-specific CD4+ T cells in malaria patients that will aid further analysis of the role of CD4+ T cells during malaria.

Histone Deacetylase Inhibitors Induce Immuno-Dominant Suppression of Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 456-456 ◽  
Author(s):  
Pavan Reddy ◽  
Yoshinobu Maeda ◽  
Raimon Duran-Struuck ◽  
Oleg Krijanovski ◽  
Charles Dinarello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Hdac Inhibitors ◽  
Class Ii ◽  
Wild Type ◽  
Tnf Α

Abstract We and others have recently demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor with anti-neoplastic properties, reduces experimental acute graft-versus-host disease (GVHD). We have now investigated the mechanisms of action of two HDAC inhibitors, SAHA and ITF 2357, on allogeneic immune responses. Bone marrow derived dendritic cells (DCs) were preincubated with the HDAC inhibitors at nanomolar concentrations for 16–18 hours and stimulated with lipopolysaccharide (LPS). Pretreatment of DCs caused a significant reduction in the secretion of TNF-α, IL-12p70 and IL-6 compared to the untreated controls (P< 0.005). Similar effects were seen using human peripheral blood mononuclear cell derived DCs. Pre-treatment of both murine and human DCs also significantly reduced their in vitro stimulation of allogeneic T cells as measured by proliferation and IFN-γ production (P<0.01). We determined the in vivo relevance of these observations utilizing a mouse model where the responses of allogeneic donor bm12 T cells depended on the function of injected host B6 DCs would stimulate. Recipient Class-II −/− B6 (H-2b) received 11 Gy on day -1 and were injected with 4–5 x 106 wild type B6 DCs treated with SAHA or with media on days -1 and 0 and then transplanted with 2 x 106 T cells and 5 x 106 TCDBM cells from either syngeneic B6 or allogeneic bm12 donors. SAHA treatment of DCs significantly reduced expansion of allogeneic donor CD4+ T cells on day +7 after BMT compared to controls (P<0.05). SAHA treatment induced a similarly significant reduction in the expansion of CD8+ cells in Class I disparate [bm1→β2M−/−] model. In vitro, SAHA treatment significantly suppressed the expression of CD40 and CD80 but did not alter MHC class II expression. Surprisingly, when mixed with normal DCs at 1:1 ratio, SAHA treated DCs dominantly suppressed allogeneic T cell responses. The regulation of T cell proliferation was not reversible by addition of IL-12, TNF-α, IL-18, anti-IL-10 or anti-TGFβ, either alone or in combination. Suppression of allogeneic responses was contact dependent in trans-well experiments. To address whether the regulation of SAHA treated DCs required contact with T cells, we devised a three cell experiment where SAHA treated DCs lacked the capacity to present antigens to T cells. DCs from B6 MHC Class II deficient (H-2b) were treated with SAHA and co-cultured with wild type B6 (H-2b) DCs along with purified allogeneic BALB/c (H-2d) CD4+ T cells in an MLR. Allogeneic CD4+ T cells proliferated well, demonstrating the regulation to be dependent on contact between SAHA treated DCs and T cells. To address the in vivo relevance of this suppression, we utilized a well characterized [BALB/c →B6] mouse model of acute GVHD. Recipient B6 animals received 11Gy on day -1 and were injected with of 5 million host type SAHA treated or control DCs on days −1, 0, and +2. Mice were transplanted on day 0 with 2 x 106 T cells and 5 x 106 BM from either syngeneic B6 or allogeneic BALB/c donors. Injection of SAHA treated DCs resulted in significantly better survival (60% vs. 10%, P < 0.01) and significantly reduced serum levels of TNF-α, donor T cell expansion and histopathology of GVHD on day +7 after BMT compared to the controls. We conclue that HDAC inhibitors are novel immunomodulators that regulate DC function and might represent a novel strategy to prevent GVHD.

Self-recognition is crucial for maintaining the peripheral CD4+ T-cell pool in a nonlymphopenic environment

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 270-277 ◽  
Author(s):  
Bruno Martin ◽  
Chantal Bécourt ◽  
Boris Bienvenu ◽  
Bruno Lucas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Cell Pool ◽  
Self Recognition ◽  
Mhc Class Ii Molecules

The role of self-recognition in the maintenance of the peripheral CD4+ T-cell pool has been extensively studied, but no clear answer has so far emerged. Indeed, in studies of the role of self-major histocompatibility complex (MHC) molecules in CD4+ T-cell survival, several parameters must be taken into account when interpreting the results: (1) in a lymphopenic environment, observations are biased by concomitant proliferation of T cells arising in MHC-expressing mice; (2) the peripheral T-cell compartment is qualitatively and quantitatively different in nonlymphopenic, normal, and MHC class II-deficient mice; and (3) in C57BL/6 Aβ-/- mice (traditionally considered MHC class II-deficient), the Aα chain and the Eβ chain associate to form a hybrid AαEβ MHC class II molecule. In light of these considerations, we revisited the role of interactions with MHC class II molecules in the survival of peripheral CD4+ T cells. We found that the answer to the question “is self-recognition required for CD4+ T cells to survive?” is not a simple yes or no. Indeed, although long-term survival of CD4+ T cells does not depend on self-recognition in lymphopenic mice, interactions with MHC class II molecules are required for maintaining the peripheral CD4+ T-cell pool in a nonlymphopenic environment. (Blood. 2006;108:270-277)

KEL RBC Transfusion Induces IgG Anti-KEL Antibodies Independent Of CD4 T Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 41-41 ◽  
Author(s):  
Sean R. Stowell ◽  
Kathryn R. Girard-Pierce ◽  
Connie M Arthur ◽  
Nicole H. Smith ◽  
James C. Zimring ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Potential Role ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Isotype Control ◽  
Rbc Transfusion

Abstract Background While red blood cells (RBCs) transfusion can provide life saving therapy, patients who require chronic transfusion therapy may develop RBC alloantibodies that limit the availability of compatible RBCs for future transfusion and increase the risk of hemolytic transfusion reactions. However, not all patients generate alloantibodies following RBC exposure. Among factors that potentially influence RBC alloantibody formation, several studies suggest that a recipient’s MHC class II repertoire may predict an individual’s likelihood of responding to a particular RBC alloantigen. However, whether MHC class II antigens are required for efficient alloantibody formation following RBC transfusion remains unknown. As a result, we examined the potential role of MHC class II in the development of RBC alloantibodies following transfusion in a murine model of KEL alloimmunization. Methods RBCs transgenically expressing the human KEL antigen specifically under a β-globin promoter (KEL RBCs) were transfused into C57BL/6, C57BL/6 MHC class II knock out (KO) or KEL transgenic control recipients. Following transfusion, blood was harvested on days 3, 5, 7, 14, 21 and 28 following transfusion and serum was analyzed for IgM or IgG anti-KEL antibodies by indirect immunofluorescence using flow cytometry with KEL and control C57BL/6 RBCs as targets. To deplete CD4 T cells, mice were injected with anti-CD4 (clone GK1.5) 4 and 2 days prior to transfusion. As a control, additional C57BL/6 recipients were similarly injected with an isotype control. C57BL/6 recipients were also injected in parallel with GK1.5 or isotype control followed by splenocyte examination for CD4 T cell depletion using anti-CD3 and an anti-CD4 clone that recognizes a different CD4 epitope than GK1.5 (clone RM4-5). All experiments were completed at least three times with 3–5 recipients per group per experiment. Results Transfusion of KEL RBCs resulted in significant IgM anti-KEL antibody formation that peaked approximately 5 days following transfusion in both C57BL/6 and C57BL/6 MHC class II KO recipients. Similarly, IgG anti-KEL antibodies could also be detected in C57BL/6 or C57BL/6 MHC class II KO as early as 7 days following transfusion and continued to rise to similar peak levels within 14 to 21 days following KEL RBC transfusion. Injection of GK1.5, but not isotype control antibody, depleted CD4 T cells to less than 1% of their original level. Transfusion of KEL RBCs into C57BL/6, CD4 depleted C57BL/6 or isotype control treated C57BL/6 resulted in similar levels of IgM anti-KEL antibody that peaked approximately 5 days following transfusion. Likewise, transfusion of KEL RBCs induced similar levels of IgG anti-KEL antibodies within 7 days following transfusion that also peaked between 14 and 21 days in C57BL/6, CD4 depleted C57BL/6 or isotype control treated C57BL/6 recipients. (All the above differences achieved a p value of <0.05) Conclusions Despite the potential role of CD4 T cells in facilitating RBC alloantibody formation, these results suggest that significant IgG RBC alloantibody can occur independent of MHC class II or CD 4 T cells. Although it remains possible that CD4 T cells become activated following RBC alloantigen exposure, the lack of CD4 T cell requirement in this model suggests that some patients may be capable of mounting a clinically significant immune response following RBC transfusion in the absence of CD4 T cell help. As a result, MHC antigen presentation of unique RBC alloantigens may not be necessary for RBC alloimmunization to occur. Disclosures: Zimring: Immucor Inc.: Research Funding; Terumo: Research Funding; Haemonetics: Consultancy; Cerus: Honoraria.

scholarly journals CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 4073-4082 ◽  
Author(s):  
Katharina N. Steinitz ◽  
Pauline M. van Helden ◽  
Brigitte Binder ◽  
David C. Wraith ◽  
Sabine Unterthurner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Structural Features ◽  
Cd4 T Cell ◽  
T Cell Epitopes ◽  
Mhc Class Ii Molecules

Abstract Today it is generally accepted that B cells require cognate interactions with CD4+ T cells to develop high-affinity antibodies against proteins. CD4+ T cells recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4+ T cells that can bind to the MHC class II–peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4+ T-cell epitopes presented by HLA-DRB1*1501 to CD4+ T cells during immune responses against FVIII. CD4+ T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays.

scholarly journals Endothelial Cells Modify the Costimulatory Capacity of Transmigrating Leukocytes and Promote Cd28-Mediated Cd4+ T Cell Alloactivation

1999 ◽  
Vol 190 (4) ◽  
pp. 555-566 ◽  
Author(s):  
Mark D. Denton ◽  
Christopher S. Geehan ◽  
Steve I. Alexander ◽  
Mohamed H. Sayegh ◽  
David M. Briscoe
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Cell Surface ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Cell Surface Expression ◽  
Lymphocyte Function

Activated vascular endothelial cells (ECs) express major histocompatibility complex (MHC) class II molecules in vitro and in vivo in acute and chronic allograft rejection. However, human ECs may be limited in their ability to effectively activate CD4+ T cells, because they do not express members of the B7 family (CD80 and CD86) of costimulatory molecules. In this study, we show that ECs promote the full activation of CD4+ T cells via trans-costimulatory interactions. By reverse transcriptase polymerase chain reaction, Western blot, and FACS® analysis, we could not detect the expression of CD80 and CD86 on activated ECs and found minimal expression on purified CD4+ T cells. In contrast, both CD80 and CD86 were expressed in allogeneic CD4+ T cell–EC cocultures. Expression of CD86 peaked at early times between 12 and 24 h after coculture, whereas CD80 was not expressed until 72 h. Addition of anti-CD86 but not anti-CD80 monoclonal antibodies to cocultures inhibited IL-2 production and the proliferation of CD4+ T cells to allogeneic donor human umbilical vein ECs (HUVECs), as well as to skin and lung microvascular ECs. Furthermore, we found that interferon γ–activated ECs but not untreated ECs induced mRNA and cell surface expression of CD80 and CD86 on CD4+ T cells, and these T cells were functional to provide a trans-costimulatory signal to autologous CD4+ T cells. Blockade of MHC class II and lymphocyte function–associated antigen 3 but not other EC cell surface molecules on IFN-γ–activated ECs inhibited the induction of CD86 on CD4+ T cells. Transmigration of purified populations of monocytes across EC monolayers similarly resulted in the induction of functional CD86, but also induced the de novo expression of the cytokines interleukin (IL)-1α and IL-12. In addition, EC-modified monocytes supported enhanced proliferation of allogeneic and autologous CD4+ T cells. Taken together, these data define the ability of the endothelium to modify CD4+ T cells and monocytes for trans-costimulatory events. This unique function of the endothelium in alloimmune T cell activation has functional consequences for the direct and the indirect pathways of allorecognition.

scholarly journals Generation of PLZF+ CD4+ T cells via MHC class II–dependent thymocyte–thymocyte interaction is a physiological process in humans

2009 ◽  
Vol 207 (1) ◽  
pp. 237-246 ◽  
Author(s):  
You Jeong Lee ◽  
Yoon Kyung Jeon ◽  
Byung Hyun Kang ◽  
Doo Hyun Chung ◽  
Chung-Gyu Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Zinc Finger Protein ◽  
Cell Subset ◽  
Cell Receptor ◽  
Class Ii ◽  
Inkt Cells ◽  
Mhc Class Ii Molecules

Human thymocytes, unlike mouse thymocytes, express major histocompatibility complex (MHC) class II molecules on their surface, especially during the fetal and perinatal stages. Based on this observation, we previously identified a novel developmental pathway for the generation of CD4+ T cells via interactions between MHC class II–expressing thymocytes (thymocyte–thymocyte [T–T] interactions) with a transgenic mouse system. However, the developmental dissection of this T–T interaction in humans has not been possible because of the lack of known cellular molecules specific for T–T CD4+ T cells. We show that promyelocytic leukemia zinc finger protein (PLZF) is a useful marker for the identification of T–T CD4+ T cells. With this analysis, we determined that a substantial number of fetal thymocytes and splenocytes express PLZF and acquire innate characteristics during their development in humans. Although these characteristics are quite similar to invariant NKT (iNKT) cells, they clearly differ from iNKT cells in that they have a diverse T cell receptor repertoire and are restricted by MHC class II molecules. These findings define a novel human CD4+ T cell subset that develops via an MHC class II–dependent T–T interaction.

510 Helping the killers: innovative cancer immunotherapy harnessing quasi-universal tumor antigen-specific CD4 T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A546-A546
Author(s):  
Margaux Saillard ◽  
Amelie Cachot ◽  
Georg Alexander Rockinger ◽  
Philippe Guillaume ◽  
Julien Schmidt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Mhc Class Ii ◽  
Tumor Antigen ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Cell Clones ◽  
Mhc Class Ii Molecules

BackgroundWhile cancer immunotherapy has mainly focused on exploiting CD8 T cells given their role in the direct elimination of tumor cells, increasing evidence highlights the crucial roles played by CD4 T cells in anti-tumor immunity. However, their very low frequency, the lack of robust algorithms to predict peptide binding to MHC class II molecules and the high polymorphism of MHC class II molecules render the study and use of circulating tumor antigen-specific CD4 T cells challenging. In this regard, the HLA-DRB3*02:02 gene encoding an HLA allele that is expressed by half of the Caucasian population, offers a way to identify CD4 T cell-defined tumor antigens with broad cancer patient coverage.MethodsHere, we aim to identify, isolate and functionally characterize ‘quasi-universal’ human tumor antigen-specific HLA-DRB3*02:02-restricted CD4 T cells in cancer patients. Using an algorithm we recently developed in house,1 tumor-associated antigenic peptides binding to this allele are identified. We have generated a large collection of HLA-DRB3*02:02-restricted CD4 T cell clones of different tumor-antigen specificities. We will perform in vitro co-cultures of CD4 T cell clones with tumor cells to measure cytokine secretion, their tumor cell killing and their phenotypic profile (PD-1, TIM3, TIGIT, 4-1BB, CD40L, LAG3, VISTA, OX40). We will sequence and clone the TCR of the most promising candidates for adoptive cell transfer therapy. Lastly, we will directly evaluate the presence of these cells ex-vivo and longitudinally monitor them in patients.ResultsN/AConclusionsTogether, these results should contribute valuable targets for coordinated CD4 and CD8 T cell-based immunotherapy of cancer.ReferenceRacle, J., et al., Robust prediction of HLA class II epitopes by deep motif deconvolution of immunopeptidomes. Nat Biotechnol 2019. 37(11): p. 1283–1286.

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