scholarly journals PD-1+ memory phenotype CD4+ T cells expressing C/EBPα underlie T cell immunodepression in senescence and leukemia

2009 ◽  
Vol 106 (37) ◽  
pp. 15807-15812 ◽  
Author(s):  
Kenichiro Shimatani ◽  
Yasuhiro Nakashima ◽  
Masakazu Hattori ◽  
Yoko Hamazaki ◽  
Nagahiro Minato

Although altered T cell function plays a part in immunosenescence, the mechanisms remain uncertain. Here we identify a bona fide age-dependent PD-1+ memory phenotype (MP) CD4+ T cell subpopulation that hardly proliferates in response to T cell receptor (TCR) stimulation and produces abundant osteopontin at the cost of typical T cell lymphokines. These T cells demonstrate impaired repopulation in Rag2−/− mice, but a homeostatic proliferation in γ-ray–irradiated mice. These T cells also reveal a unique molecular signature, including a strong expression of C/EBPα normally expressed in myeloid-lineage cells, with diminished c-Myc and cyclin D1. Transduction of Cebpa in regular CD4+ T cells inhibited the TCR-mediated proliferation with c-Myc and cyclin D1 repression and caused a striking activation of Spp1 encoding osteopontin along with concomitant repression of T cell lymphokine genes. Although these T cells gradually increase in number with age and become predominant at the senescent stage in normal mice, the generation is robustly accelerated during leukemia. In both conditions, their predominance is associated with the diminution of specific CD4+ T cell response. The results suggest that global T cell immunodepression in senescence and leukemia is attributable to the increase in PD-1+ MP CD4+ T cells expressing C/EBPα.

1993 ◽  
Vol 177 (2) ◽  
pp. 257-263 ◽  
Author(s):  
D Dunon ◽  
M D Cooper ◽  
B A Imhof

Current evidence suggests both thymic and extrathymic origins for T cells. Studies in mice favor an in situ origin for a prominent population of intestinal intraepithelial lymphocytes that express gamma/delta T cell receptor (TCR). This developmental issue is explored in an avian model in which the gamma/delta lymphocytes constitute a major T cell subpopulation that is accessible for study during the earliest stages of lymphocyte development. In the chick embryo, cells bearing the gamma/delta TCR appear first in the thymus where they reach peak levels on days 14-15 of embryogenesis, just 2 d before gamma/delta T cells appear in the intestine. Using two congenic chick strains, one of which expresses the ov antigen, we studied the origin and kinetics of intestinal colonization by gamma/delta T cells. The embryonic gamma/delta+ thymocytes homed to the intestine where they survived for months, whereas an embryonic gamma/delta- thymocyte population enriched in thymocyte precursors failed to give rise to intestinal gamma/delta+ T cells. Embryonic hemopoietic tissues, bone marrow, and spleen, were also ineffective sources for intestinal gamma/delta+ T cells. Intestinal colonization by gamma/delta+ thymocytes occurred in two discrete waves in embryos and newly hatched birds. The data indicate that intestinal gamma/delta T cells in the chicken are primarily thymic migrants that are relatively long-lived.


2007 ◽  
Vol 81 (22) ◽  
pp. 12504-12514 ◽  
Author(s):  
Derek D. Sloan ◽  
Keith R. Jerome

ABSTRACT Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-κB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.


Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2053-2061 ◽  
Author(s):  
Laura Crompton ◽  
Naeem Khan ◽  
Rajiv Khanna ◽  
Laxman Nayak ◽  
Paul A. H. Moss

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.


2020 ◽  
Vol 6 (27) ◽  
pp. eaaz7809 ◽  
Author(s):  
Jan A. Rath ◽  
Gagan Bajwa ◽  
Benoit Carreres ◽  
Elisabeth Hoyer ◽  
Isabelle Gruber ◽  
...  

Transgenic coexpression of a class I–restricted tumor antigen–specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity of CD4+ T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4+ T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4+ and CD8+ T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8+ T cell function and preserved less differentiated CD4+ and CD8+ T cells after tumor challenge. TCR8+CD4+ T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation– and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.


Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2244-2253 ◽  
Author(s):  
Michael Rist ◽  
Corey Smith ◽  
Melissa J. Bell ◽  
Scott R. Burrows ◽  
Rajiv Khanna

Abstract The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3711-3711
Author(s):  
Julia Neudorfer ◽  
Daniel Sommermeyer ◽  
Christian Peschel ◽  
Thomas Blankenstein ◽  
Wolfgang Uckert ◽  
...  

Abstract The gene transfer of alpha and beta chains derived from a defined TCR has been successfully applied to endow T cells with specificities directed against tumor-associated antigens. However, it is still unclear if the transfer of TCR genes into T cells that already express an endogenous TCRalpha and beta chain leads to engineered T cells expressing four different TCR complexes on their cell surface. Mixed TCR heterodimers composed of endogenous and exogenous TCR chains may acquire new specificities, which may cause unwanted reactions in patients following adoptive T cell transfer. We examined the possibility of mixed TCR heterodimer formation using defined conditions of single TCR chain transfer into human cytotoxic T cell (CTL) clones specific for CMV and Melan-A, respectively. After stimulation for three days CTLs were retrovirally transduced with the beta chain derived from a gp100-specific TCR. The expression of the exogenous (transduced) and the endogenous beta chain was distinguished by flow cytometry using antibodies against the different Vbeta motives. Indeed, CTLs that had been transduced with the single beta chain expressed this chain on the cell surface indicating the formation of mixed TCRs, because the expression of the exogenous TCRbeta chain requires the pairing with the endogenous TCRalpha chain. Furthermore, we transduced the CTL clones with both the TCRalpha and beta chain derived from a gp100-specific TCR. The transduced T cells were positively stained with an A2/gp100 multimer documenting the correct formation of the exogenous TCR chains. Functionality of transduced CTL clones was tested by antigen-specific IFN-gamma release and cytolytic activity. The TCR-transduced T cells were sorted with the A2/gp100 multimer and expanded for two weeks. Double staining with HLA multimers for the endogenous and the transduced TCRs showed the downregulation of the endogenous TCRs in three different CTL clones. In one CTL clone, the endogenous TCR was even replaced by the exogenous TCR as documented by flowcytometry and antigen-specific T cell function. In conclusion, transfer of single TCR chains in CTL clones can result in the formation of TCR heterodimers. However, our results also show that complete TCRs are predominantly expressed or can even replace other TCRs following transfer. The development of dominant TCRs will facilitate the therapeutical approaches of adoptive transfer regimens based on TCR-transduced T cells, because dominant TCRs can be selected or TCRs can be modified to be more dominant.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11563-11563 ◽  
Author(s):  
Elias Obeid ◽  
Chun Zhou ◽  
Alexander Macfarlane ◽  
R. Katherine Alpaugh ◽  
Cecilia McAleer ◽  
...  

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.


1998 ◽  
Vol 1 (6) ◽  
pp. 1-20 ◽  
Author(s):  
Julian K. Hickling

T lymphocytes (T cells) play critical roles in the regulation of immune responses, and are responsible for mediating many of the effector mechanisms of the immune system. For this reason, there has always been a need for assays to measure accurately the activity of populations of T cells, both in model (animal) systems and in humans. The expansion of the biotechnology industry has led to a dramatic increase in the number of novel immunotherapeutics that are being developed for the treatment of cancer, autoimmune disorders and infectious diseases. This increase in activity in the field of immunotherapy, coupled with the expense of clinical trials, has led to renewed interest in methods that accurately assess T-cell function, as researchers seek to maximise the amount of information that can be obtained from each clinical study. Assessing the quantitative and qualitative nature of a T-cell response, for example following vaccination or immunosuppressive therapy, can provide valuable information about the efficacy of a treatment, in place of a clinical endpoint. This article reviews some of the established methods that are used to monitor human T-cell activity, and describes some new approaches that are in development to increase the speed, sensitivity and relevance of such methods.


2007 ◽  
Vol 204 (8) ◽  
pp. 1787-1801 ◽  
Author(s):  
Jae-Ho Cho ◽  
Onur Boyman ◽  
Hee-Ok Kim ◽  
Bumsuk Hahm ◽  
Mark P. Rubinstein ◽  
...  

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen–self–major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced “homeostatic” proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8+ T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.


Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3528-3537 ◽  
Author(s):  
Maryam Ahmadi ◽  
Judith W. King ◽  
Shao-An Xue ◽  
Cécile Voisine ◽  
Angelika Holler ◽  
...  

Abstract The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.


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