Epitope specificity and Ia restriction of T cell responses to insulin in a system of complementing Ir genes: analysis with primed lymph node T cells and a long-term cultured T cell line

1983 ◽  
Vol 13 (9) ◽  
pp. 756-761 ◽  
Author(s):  
Eberhard Spaeth ◽  
Erwin Rüde
2016 ◽  
Vol 84 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
Charles S. Rosenberg ◽  
Weibo Zhang ◽  
Juan M. Bustamante ◽  
Rick L. Tarleton

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.


2015 ◽  
Vol 89 (7) ◽  
pp. 3542-3556 ◽  
Author(s):  
Timothée Bruel ◽  
Chiraz Hamimi ◽  
Nathalie Dereuddre-Bosquet ◽  
Antonio Cosma ◽  
So Youn Shin ◽  
...  

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.


2004 ◽  
Vol 173 (1) ◽  
pp. 673-681 ◽  
Author(s):  
Insoo Kang ◽  
Myung Sun Hong ◽  
Helena Nolasco ◽  
Sung Hwan Park ◽  
Jin Myung Dan ◽  
...  

2020 ◽  
Vol 8 (2) ◽  
pp. e001133
Author(s):  
Esmé TI van der Gracht ◽  
Mark JA Schoonderwoerd ◽  
Suzanne van Duikeren ◽  
Ayse N Yilmaz ◽  
Felix M Behr ◽  
...  

BackgroundAdenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8+ T cells elicited upon immunization with adenoviral vectors.MethodsAdenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (107, 108 or 109 infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated.ResultsThe adenoviral vaccines elicited inflationary E7-specific memory CD8+ T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8+ T cells in the circulation related to the development of E7-specific CD8+ tissue-resident memory T (TRM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8+ T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8+ TRM cells. Moreover, the formation of CD8+ TRM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization.ConclusionsTogether, these data show that adenoviral vector-induced CD8+ T cell inflation promotes protective TRM cell populations, and this can be enhanced by targeting CTLA-4.


2005 ◽  
Vol 79 (10) ◽  
pp. 5988-5995 ◽  
Author(s):  
Rahnuma Wahid ◽  
Martin J. Cannon ◽  
Marie Chow

ABSTRACT The presence of poliovirus (PV)-specific CD4+ T cells in individuals vaccinated against polio has been shown, but CD8+ T-cell responses have not been described. Here, we functionally characterize the CD4+ T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8+ T-cell responses in vitro from vaccinees. Both CD4+ T and CD8+ T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway. Furthermore, the T cells also recognize and kill Sabin 1 vaccine-infected targets. The macrophage-stimulated CD4+ T and CD8+ T cells most likely represent memory T cells that persist for long periods in vaccinated individuals. Thus, immunity to PV vaccination involves not only an effective neutralizing antibody titer but also long-term CD4+ and CD8+ cytotoxic T-cell responses.


2021 ◽  
Vol 17 (12) ◽  
pp. e1010137
Author(s):  
Alexander C. Dowell ◽  
Tracey A. Haigh ◽  
Gordon B. Ryan ◽  
James E. Turner ◽  
Heather M. Long ◽  
...  

Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral carriage is associated with several malignancies and certain autoimmune diseases. Current efforts developing EBV prophylactic vaccination have focussed on neutralising antibodies. An alternative strategy, that could enhance the efficacy of such vaccines or be used alone, is to generate T-cell responses capable of recognising and eliminating newly EBV-infected cells before the virus initiates its growth transformation program. T-cell responses against the EBV structural proteins, brought into the newly infected cell by the incoming virion, are prime candidates for such responses. Here we show the structural EBV capsid proteins BcLF1, BDLF1 and BORF1 are frequent targets of T-cell responses in EBV infected people, identify new CD8+ and CD4+ T-cell epitopes and map their HLA restricting alleles. Using T-cell clones we demonstrate that CD4+ but not CD8+ T-cell clones specific for the capsid proteins can recognise newly EBV-infected B-cells and control B-cell outgrowth via cytotoxicity. Using MHC-II tetramers we show a CD4+ T-cell response to an epitope within the BORF1 capsid protein epitope is present during acute EBV infection and in long-term viral carriage. In common with other EBV-specific CD4+ T-cell responses the BORF1-specific CD4+ T-cells in IM patients expressed perforin and granzyme-B. Unexpectedly, perforin and granzyme-B expression was sustained over time even when the donor had entered the long-term infected state. These data further our understanding of EBV structural proteins as targets of T-cell responses and how CD4+ T-cell responses to EBV change from acute disease into convalescence. They also identify new targets for prophylactic EBV vaccine development.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2942-2942
Author(s):  
Jessica Lorente ◽  
Divya Kannegenti ◽  
Brandon Theall ◽  
Lisandra Hernandez ◽  
Esha Vallabhaneni ◽  
...  

Abstract Aplastic Anemia (AA) is an immune-mediated and life-threatening form of acquired bone marrow failure. AA ranges from moderate to severe AA, and is characterized by development and expansion of self-reactive effector T cells, which cause apoptosis of mature blood cells, progenitors and hematopoietic stem cells (HSCs). Current treatments for AA, which are not always effective or feasible, include immunosuppressive therapy (IST) and allogeneic HLA-identical sibling or well-matched unrelated donor BM transplant. Because the self-antigens triggering AA remain to be identified, mouse lymphocyte infusion models of AA with striking similarities to human AA have been developed utilizing alloantigen recognition. The AA in these models is induced by infusing lymph node cells (LNCs) from C57BL/6J mice into MHC partially mismatched F1 hybrid B6D2F1 or CByB6F1 recipients, or into minor-H antigen mismatched C.B10 recipients. The host mice develop SAA without any clinical signs of generalized GVHD, and characterized by BM infiltration and oligoclonal expansion of donor effector T cells, apoptosis of all host BM cells, severe BM aplasia and death within 3-5 weeks after LNC infusion. These preclinical mouse models represent a very useful in vivo system for testing new therapeutic approaches to treat and manage SAA. Activation of self-reactive T cells in human AA and alloreactive donor T cells in mouse AA models involves interaction of T cells with dendritic cells (DCs) as professional APCs. DCs express β2 integrin CD11b/CD18 (Mac-1), which plays an important role in inflammation, cell-mediated killing and cell activation. Notably, Mac-1 expressed on DCs is inactive and is not activated on contact with T cells. More importantly, activation of Mac-1 on DCs by Mg2+ treatment significantly reduces their T cell-activating capacity, and active CD11b represses DC cross-priming of cytotoxic T cells. Thus, activation of Mac-1 on DCs represents a potential new immunosuppressive strategy for reducing pathological T cell responses in AA. Dr. Gupta has identified novel Mac-1 agonists, termed Leukadherins (LAs1-3) that bind to and activate Mac-1. Multiple lines of experimental evidence generated by Dr. Gupta’s and Dr. Jurecic’s groups have shown that LAs have potent anti-inflammatory and immunosuppressive properties. For example, treatment with LA1 is safely and effectively reducing the onset and severity of Experimental Autoimmune Encephalomyelitis (EAE) in mice, induced by Myelin Oligodendrocyte Glycoprotein (MOG). Moreover, in EAE mice LA1 efficiently decreased the activation of myelin-reactive T cells and their IFN-γ production. We hypothesized that by activating Mac-1 on DCs LAs could effectively (a) reduce T cell-activating capacity of DCs and attenuate allo-reactive T cell responses, and (b) reduce severity of AA in mouse models. Indeed, in mixed lymphocyte reaction, which depends on stimulation of allogeneic T cells by DCs, LA1 significantly suppressed proliferation of lymph node T cells from C57BL6/J mice in the presence of irradiated splenocytes from allogeneic DBA/2J mice. SAA was induced in B6D2F1 mice by tail vein injection of 5 x 10e7 LNCs from C57BL/6J mice. The untreated AA mice died within 21 days of LNC infusion and exhibited (a) severe BM aplasia, (b) ~5-fold expansion of CD4+ T cells and >20-fold expansion of CD8+ T cells in comparison to Control B6D2F1 mice, and (c) severe depletion of HSCs (LSK CD150+ CD48- BM cells); Multipotent progenitors (MPPs, LSK CD150- CD48- BM cells); and Hematopoietic progenitors (HPC-1, LSK CD150- CD48+ cells; HPC-2, LSK CD150+ CD48+ cells). In contrast, AA mice treated IP with 1 mg/kg/day of LA1 for 7 or 21 days after LNC infusion exhibited (a) mild BM aplasia and improved BM cellularity, (b) significantly reduced expansion of CD4 (~2-fold) and CD8 (~12-fold) T cells in the BM, and (c) significantly improved frequency and total numbers of HSCs and progenitors in comparison to untreated AA mice. More importantly, treatment of AA mice with LA1 for 21 days resulted in 40-50% of AA mice surviving for more than 7 weeks after LNC infusion. These results demonstrate that treatment with LA1 can safely convert SAA into a moderate disease in preclinical mouse AA models and provide a platform for testing of LAs as new alternative or adjuvant therapy to manage ongoing AA in patients who (1) are not responding to IST and are not candidates for BMT, and/or (2) are undergoing IST and awaiting BMT. Disclosures No relevant conflicts of interest to declare.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2537-2537
Author(s):  
T. B. Hunter ◽  
R. P. Gladue ◽  
S. J. Antonia

2537 Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer. No significant financial relationships to disclose.


BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Krishna Das ◽  
David Eisel ◽  
Mathias Vormehr ◽  
Karin Müller-Decker ◽  
Adriane Hommertgen ◽  
...  

Abstract Background NY-BR-1 has been described as a breast cancer associated differentiation antigen with intrinsic immunogenicity giving rise to endogenous T and B cell responses. The current study presents the first murine tumor model allowing functional investigation of NY-BR-1-specific immune responses in vivo. Methods A NY-BR-1 expressing tumor model was established in DR4tg mice based on heterotopic transplantation of stable transfectant clones derived from the murine H2 compatible breast cancer cell line EO771. Composition and phenotype of tumor infiltrating immune cells were analyzed by qPCR and FACS. MHC I binding affinity of candidate CTL epitopes predicted in silico was determined by FACS using the mutant cell line RMA-S. Frequencies of NY-BR-1 specific CTLs among splenocytes of immunized mice were quantified by FACS with an epitope loaded Db-dextramer. Functional CTL activity was determined by IFNγ catch or IFNγ ELISpot assays and statistical analysis was done applying the Mann Whitney test. Tumor protection experiments were performed by immunization of DR4tg mice with replication deficient recombinant adenovirus followed by s.c. challenge with NY-BR-1 expressing breast cancer cells. Results Our results show spontaneous accumulation of CD8+ T cells and F4/80+ myeloid cells preferentially in NY-BR-1 expressing tumors. Upon NY-BR-1-specific immunization experiments combined with in silico prediction and in vitro binding assays, the first NY-BR-1-specific H2-Db-restricted T cell epitope could be identified. Consequently, flow cytometric analysis with fluorochrome conjugated multimers showed enhanced frequencies of CD8+ T cells specific for the newly identified epitope in spleens of immunized mice. Moreover, immunization with Ad.NY-BR-1 resulted in partial protection against outgrowth of NY-BR-1 expressing tumors and promoted intratumoral accumulation of macrophages. Conclusion This study introduces the first H2-Db-resctricted CD8+ T cell epitope-specific for the human breast cancer associated tumor antigen NY-BR-1. Our novel, partially humanized tumor model enables investigation of the interplay between HLA-DR4-restricted T cell responses and CTLs within their joint attack of NY-BR-1 expressing tumors.


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