Direct evidence of a clonal and tumor-directed T cell response to prostate cancer brachytherapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 22-22 ◽  
Author(s):  
Scott Williams ◽  
Simon Keam ◽  
Heloise Halse ◽  
Catherine Mitchell ◽  
Franco Caramia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
High Dose Rate ◽  
T Cell Response ◽  
High Dose ◽  
T Cell Repertoire ◽  
Cell Repertoire

22 Background: We characterised the immune response in human prostate cancer (PC) to high dose rate brachytherapy (HDRBT) using serial pre- and post-HDRBT biopsies. Methods: Prostate biopsies and peripheral blood samples were obtained from 9 men with clinically localised PC at baseline and again 14 days following a 10 Gy fraction of HDRBT. Immune infiltrates were characterised using multiplex immunohistology (T cell and pan-immune panels) and targeted gene expression profiling (Nanostring pan-cancer immune panel). T cell repertoire was assessed using T cell receptor (TCR) Vbeta CDR3 deep sequencing. Results: HDRBT induced profound but heterogenous immune responses. At the extremes, one patient had an extensive tumor-infiltrating lymphocyte (TIL) response post-HDRBT, comprising T cells (CD4+ > CD8+ > Treg), B cells, and PDL1+ antigen presenting cells (macrophages and CD11c+ dendritic cells); another had a substantial baseline immune infiltrate eliminated by HDRBT. TIL-hi cases (either before or after HDRBT) had a conserved signature of T cell activation, differentiation, and trafficking, with upregulation of checkpoint molecules PD1, IDO1, BTLA, CTLA4, ICOS, B7-H3 and FoxP3. Those TIL-hi specifically in response to HDRBT also had down-regulation of genes regulating myeloid differentiation and granulocyte chemotaxis pre-HDBRT. Conversely, a monocyte-like myeloid-derived suppressor cell signature was seen in the TIL-lo responders. The median number of dominant clones ( > 1% prevalence) determined by TCR sequencing was 24.5 and 26.5 pre- and post-HDRBT respectively. Only 2 clones (in 1 patient) were present at both time points with the T cell repertoire otherwise being completely new following HDRBT. A subset of PC-associated T cell dominant clones was also present in the PB in all patients, suggesting HDRBT can induce systemic immunity. Conclusions: We have shown that treatment of localized prostate cancer with HDRBT induces a marked clonal TIL infiltrate dominated by T cells likely to be operating under the control of multiple checkpoints. These first-in-human data may be able to inform the rational selection of immunotherapy to combine with HDRBT.

Increased Activity in the T Cell Effector Phase and Enhanced T Cell Repertoire Target-Tissue Stability Distinguish Alloreactivity Across Major Versus Minor Histocompatibility Barriers

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4284-4284
Author(s):  
Pingping Zheng ◽  
Adrianne E Vasey ◽  
Jeanette Baker ◽  
Bettina Iliopoulou ◽  
Dennis B Leveson-Gower ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Shannon Index ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Effector Phase ◽  
Donor T Cells ◽  
Tcr Repertoire

Abstract Graft-versus-host disease (GVHD) occurs when transplanted donors' T cells recognized the recipients' antigens and damaged host tissues and cells, particularly the skin, gut and liver in the acute setting. Although it is well known GVHD is more aggressive and manifests more quickly across major versus minor histocompatibility barrier, little is known comparatively about the donor T cell activation and T cell repertoire changes. To investigate temporal and spatial events of GHVD development, side-by-side transplants were conducted into major and minor-mismatched murine recipients (Balb.c and Balb.b) using hematopoietic cells from the same donor strain(B6). In both models, T cells home to nodal sites by day 3, proliferate, and exit to GVHD target tissues by day 6. Additionally, expression of homing and activation markers was equivalent for all markers examined on day 3. However, tissue migration and proliferation were reduced in the minor model. By day 6, minor-mismatched T cells had increased CD62L retention and reduced P-selectin and CD44 expression. We also found fewer MHC-matched T cells producing IFN-g and TNF-a. Our data show that early events of donor T cell activation are similar in both models, suggesting that the delayed onset and attenuated disease GVHD seen across minor barriers arise from temporal differences in the effector phase, rather than the initiation phase, of GVHD. To further understand the differences across major versus minor histocompatibility barriers on the T cell repertoire and patterns of T cell alloreactivity, we collected a sample of T cells from donor mice used for transplantation, and also sampled gut tissues from syngeneic, major and minor- mismatched transplanted mice on day 9, 9 and 30 respectively at times when the allogeneic groups of mice showed severe GVHD symptoms. To reduce the background of high percentage of TCR pseudogenes in mouse genome, 5'RACE starting from RNA samples and deep sequencing of TCRa and TCRb were applied to investigate whether TCR repertoire of the major and minor-mismatched mice were skewed with clonal expansion, and how among the major and minor-mismatched mice. While we hypothesized that the major MHC mismatched group would have lower diversity because of expanded clones associated with the GVHD, the shannon index of TCRa indicated gut TCR repertoire of major and minor mismatched mice have greater diversity than syngeneic group(P<0.05). We did not see differences in the shannon index of diversity on examination of the TCRb repertoire. Contrary to our expectation, that the TCR repertoire of major mismatch would be skewed towards representation of a few highly expanded clones in the gut, we in fact saw that the TCR repertoire in these mice appeared less skewed. The TCR repertoire of the gut was more highly related among individuals in the major mismatch groups than among or between the other groups. This strongly suggests a more reproducible repertoire structure. To examine if certain T cell clones were more likely to appear reproducibly in the major and/or minor mismatch setting, we compared the shared clones across the major-mismatched transplanted mice. Bhattacharyya coefficients showed that the major-mismatched mice shared more clones with the minor-mismatched group than the syngeneic groups(P<0.05). A total of eight shared TCRa clonotypes among major-mismatched mice are also detected. The common CDR3 clonotypes might be associated with GVHD. We found 7 of them are also in donor CD4 memory cells' repertoire; and one is present in both donor's CD4 and CD8 memory cells. One of the complementarity determining regions sequences is "AASYQGGRALI" which is also in common among minor-mismatched mice. We also measured the repertoire similarity between donor T cells and the gut TCR repertoires of three groups. Bhattacharyya coefficients of TCRa and TCRb between donor T cells and major-mismatched gut repertoire is greater than donor T cells with either syngeneic or minor-mismatched repertoire(P<0.05), which suggest that the major-mismatched mice has more T cells homing to gut which might be associated with GVHD. Our sequencing data showed that major and minor-mismatched transplantation might not cause the clonal expansion in the gut TCR repertoire, but their repertoire patterns are different from the syngeneic groups, which might be associated with T cell alloreactivity and GVHD. Disclosures No relevant conflicts of interest to declare.

553 CUE-100 series Immuno-STATs from concept to the clinic: Leveraging protein engineering to stimulate and selectively deliver affinity-attenuated IL-2 to antigen-specific T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A589-A589
Author(s):  
Alex Histed ◽  
Natasha Girgis ◽  
Miguel Moreta ◽  
Jonathan Soriano ◽  
BS Luke Witt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Clinical Activity ◽  
Target Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Stimulation Of

BackgroundActivation of T cells requires a specific peptide/HLA (human leukocyte antigen) signal presented by an interacting immune or target cell along with engagement of co-stimulatory molecules or cytokine receptors. Cue Biopharma has developed a proprietary biologics platform, termed Immuno-STAT™ (Selective Targeting and Alteration of T cells), wherein a singular protein framework incorporates peptide/HLA complexes and co-stimulatory or cytokine signals. The CUE-100 series Immuno-STATs selectively deliver rationally engineered IL-2 molecules to antigen-specific T cells. The IL-2 molecules in the CUE-100 series Immuno-STATs contain mutations that attenuate binding to IL-2 receptors alpha and beta, which minimizes activation of regulatory T cells (Tregs) and the irrelevant non-antigen-specific T cell repertoire. We have demonstrated that CUE-100 series Immuno-STATs specific for different antigenic peptides (from HPV16, WT1, MART-1, CMV, Flu, and HIV) induce expansion of functional, oligoclonal, antigen-specific repertoires from human PBMCs. The lead clinical candidate CUE-101, presenting the E711-20 peptide from HPV-16 in the context of HLA-A*02:01, is currently being tested in a Phase 1 clinical trial in recurrent/metastatic head and neck cancer patients with evidence of dose-proportional PK, early pharmacodynamic effects and signals of clinical activity.MethodsCUE-100 series Immuno-STATs were tested with human PBMCs to demonstrate specific T cell activation and expansion. Expanded T cell clonality was assessed by single cell TCR sequencing. Responses of T cells to peptide-presenting targets was evaluated by cytokine staining and by assessing their ability to kill target cells. In vivo activity of CUE-100 series Immuno-STATs was assessed in HLA-A2 transgenic mice.ResultsData demonstrate that the CUE-100 series Immuno-STATs selectively activate antigen-specific CD8+ T cells. Signaling, cell-based assays and cytokine release studies confirmed functional attenuation of the IL-2 components of the CUE-100 series, which allows for a favorable safety and selectivity profile. Immuno-STATs demonstrated robust expansion of CD8+ T cells after primary stimulation of unprimed hPBMCs, or re-stimulation of hPBMCs after initial cognate peptide stimulation. In addition, CUE-100 series Immuno-STATs expanded CD8+ T cells in naïve HLA-A*02 transgenic mice. In both cases the expanded T cells exhibited a polyfunctional response upon challenge with peptide-presenting target cells.ConclusionsThe presented data suggests that CUE-100 series Immuno-STATs have the potential to enhance anti-tumor immune responses by inducing a robust antigen-specific, oligoclonal, polyfunctional T cell repertoire. Early validation of CUE-100 series Immuno-STATs is obtained through the emerging signs of pharmacodynamic and clinical activity in the ongoing Phase I trial with CUE-101.ReferenceQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.

Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
Amit Adhikari ◽  
Juliete Macauley ◽  
Yoshimi Johnson ◽  
Mike Connolly ◽  
Tim Coleman ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

scholarly journals DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease

2020 ◽  
Author(s):  
M E Jacobs ◽  
J N Pouw ◽  
M A Olde Nordkamp ◽  
T R D J Radstake ◽  
E F A Leijten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Inverse Correlation ◽  
T Cell Response ◽  
Peripheral Blood Mononuclear ◽  
Psoriatic Disease

Abstract Background Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods By flow cytometry we analyzed peripheral blood mononuclear cells of patients with psoriasis (n=20) or psoriatic arthritis (n=21), and healthy individuals (n=7). We measured CD155, TIGIT and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and -negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results High CD155 expression associates with TNF production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

Prostate Cancer Immunology: Biology, Therapeutics, and Challenges

2005 ◽  
Vol 23 (32) ◽  
pp. 8262-8269 ◽  
Author(s):  
W. Scott Webster ◽  
Eric J. Small ◽  
Brian I. Rini ◽  
Eugene D. Kwon
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Advanced Prostate Cancer ◽  
Cell Activation ◽  
Tumor Regression ◽  
Prostate Cancer Treatment ◽  
Mechanistic Basis ◽  
Antigen Presenting

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.

Patients (Pts) Surviving Haploidentical Stem Cell Transplantation (SCT) after Ex Vivo Costimulatory Blockade To Induce Anergy Experience Few Long-Term Complications.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 599-599 ◽  
Author(s):  
Eva C. Guinan ◽  
John G. Gribben ◽  
Lisa L. Brennan ◽  
Lee M. Nadler
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Costimulatory Blockade ◽  
Cell Counts

Abstract Poor and delayed immune reconstitution remains a major stumbling block to successful SCT especially when alternative donors are used. Strategies to selectively remove or inactivate alloreactive cells while leaving the other donor T cell repertoire intact might address this problem. A functional T cell response requires an antigen (Ag)-specific MHC-restricted signal (signal 1) to the T cell receptor (TCR) by an Ag presenting cell (APC) as well as a second, Ag independent costimulatory signal (signal 2) provided in large part by B7 family members on APC to CD28 on T cells. Without signal 2, T cells develop tolerance to the specific Ag. Costimulation can be blocked by either CTLA4-Ig, a fusion of Ig with human CTLA4 (the T cell high affinity B7 ligand) or a combination of humanized IgG2 isotype mutated monoclonal antibodies to the APC molecules B7-1 and B7-2. In 2 pilot studies of patients (pts) undergoing haploidentical SCT, donor T cell replete BM was incubated ex vivo with recipient irradiated peripheral blood mononuclear cells with CTLA4-Ig (pilot 1) or anti-B7-1+anti-B7-2 (pilot 2) to induce alloAg specific tolerance. 19 pts age 7 mos-50 yrs (median 15 yrs) were enrolled on pilot 1 and 5 aged 4–12 (median 6) on pilot 2. 3 pts had congenital BM failure. 21 pts with malignancy, ALL (11), AML(7), NHL(2), MDS(1), were &gt;CR1and 14/21 had progressive disease (PD). Pts received TBI based ablative conditioning. Pts received a median of 3.3x106/kg CD34+ cells (0.5–12.3) containing a median of 2.8x 107/kg CD3+ (0.7–6.8), 1.6x 107/kg CD4+ (0.4–4.1), and 1x107/kg CD8+ (0.2–3.7) T cells. One pt got additional anergized cells for slow recovery and engrafted fully. One AML pt had autologous persistence and graft failure (GF). Evaluable pts engrafted at median 21 d (range, 13–29) with full donor chimerism. Of the 21 evaluable pts, 9 (43%) had findings consistent with acute GVHD graded B (n=4), C (n=4) and D (n=1) despite inconsistent pathology. GVHD symptoms were largely isolated to the GI tract and resolved with observation or moderate steroids. No death was attributable to GVHD. 11 pts died early of a combination of bacterial or fungal infection and/or regimen-related toxicity at a median of 35 d (8–159). Of the remaining 13 pts, the GF pt died after 2nd SCT elsewhere, 1 pt had sudden death d 176 at home and 2 pts with extramedullary AML died d 60 and 149 with PD. One T-ALL pt died of late PD d 1758. All BM failure and 3/14 transplanted with PD survive. All 8 survivors (8/19 &lt; 23 yrs) have 100% performance status at a median of 2423 d (1580–2875). None take medications or have chronic GVHD. 3 pts became CMV Ag + by d 100, (1 was transplanted with CMV), and responded to anti-viral therapy. Unlike many reported approaches to haploidentical SCT, aside from several CVL associated bacteremias, there have been no admissions for opportunistic infection and no late viral infections. All pts have good T cell counts, respond to vaccines and specific Ags and have good immunoglobulin levels. Costimulatory blockade, a method of limiting alloreactivity which leaves the remaining T cell repertoire intact, holds out promise as a method of overcoming alloreactivity while better preserving donor immune function and preserving anti-tumor activity. A new study combining costimulatory blockade and megadose stem cell SCT has been initiated.

DNA vaccine with pembrolizumab to elicit antitumor responses in patients with metastatic, castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 168-168 ◽  
Author(s):  
Douglas G. McNeel ◽  
Jens C. Eickhoff ◽  
Robert Jeraj ◽  
Mary Jane Staab ◽  
Jane Straus ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Flt Pet ◽  
Pet Ct

168 Background: We have previously investigated a DNA vaccine encoding prostatic acid phosphatase (PAP, pTVG-HP) in patients with PSA-recurrent prostate cancer, and have demonstrated that this can be safely administered over many months and can elicit PAP-specific T cells. A phase 2 trial is currently underway. In preclinical models, we have found that blockade of regulatory receptors, including PD-1, at the time of T cell activation with vaccination produced anti-tumor responses in vivo. Similarly, we have recently found that patients with prostate cancer previously immunized with a DNA vaccine develop PD-1-regulated T cells. These findings suggested that combined PD-1 blockade with vaccination should elicit superior anti-tumor responses in patients with prostate cancer. Methods: A clinical trial was designed to evaluate the immunological and clinical efficacy of pTVG-HP when delivered in combination or in sequence with pembrolizumab, in patients with mCRPC. Serial biopsies, blood draws, and exploratory FLT PET/CT imaging are being conducted for correlative analyses. Results: While trial accrual continues, 1 of 14 subjects has experienced a grade 3 adverse event. There have been no grade 4 events. Several patients treated with the combination have experienced serum PSA declines, and several have experienced decreases in tumor volume by radiographic imaging at 12 weeks, including one partial response. Expansion of PAP-specific Th1-biased T cells has been detected in peripheral blood samples. Exploratory FLT PET/CT imaging has demonstrated proliferative responses in metastatic lesions and in vaccine-draining lymph nodes. Evaluation of biopsy specimens for recruitment of antigen-specific T cells is currently underway. Conclusions: PD-1 pathway inhibitors have demonstrated little clinical activity to date when used as single agents for treating prostate cancer. Our findings suggest that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells, detectable within the peripheral blood and by imaging, and result in objective anti-tumor changes. Clinical trial information: NCT02499835.

scholarly journals T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells.

1988 ◽  
Vol 167 (5) ◽  
pp. 1697-1707 ◽  
Author(s):  
B Fleischer ◽  
H Schrezenmeier
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
T Cell Response ◽  
Target Cells ◽  
Beta Chain ◽  
Alpha Beta

Staphylococcal enterotoxins (SE) are the most potent mitogens for T lymphocytes known; concentrations of less than 10(-9) M are sufficient for T cell activation. The mechanism of T cell activation by SE is unknown. We have used cloned human cytotoxic and proliferative T lymphocytes to dissect the molecular mechanism of T cell activation by SE. With rare exceptions, all TCR alpha/beta chain-expressing T cell clones of CD4+ or CD8+ phenotype, as well as CD4-8- TCR alpha/beta chain negative chain-expressing T lymphocyte clones, respond with proliferation and/or cytotoxicity to SE. For triggering of all these clones, the presence of autologous or allogeneic MHC class II molecules on accessory or target cells is necessary. This requirement for class II antigens is not due to an immunological recognition of processed SE, since inhibition of antigen processing has no influence on the T cell response to SE. SE acts on the T cells directly since (a) they stimulate a rise in intracellular calcium concentration in T cell lines or purified T cells, and (b) accessory cells can be replaced by phorbolesters in the proliferative activation of resting T cells by SE. Furthermore, the T cell response to SE shows extensive clonal heterogeneity. These results suggest that SE are functionally bivalent mitogens binding highly selectively to HLA class II molecules and the TCR. Thus, compared with other polyclonal T cell activating agents, activation with SE most closely mimicks the physiological way of MHC-restricted antigen recognition by T lymphocytes.

scholarly journals Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Aurélien Azam ◽  
Sergio Mallart ◽  
Stephane Illiano ◽  
Olivier Duclos ◽  
Catherine Prades ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Anchor Residue ◽  
Hla Dr

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.

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