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Temporary CXCR3 and CCR5 antagonism following vaccination enhances memory CD8 T cell immune responses.

ABSTRACT: Although current vaccination strategies have been successful at preventing a variety of human diseases, attempts at vaccinating against some pathogens such as AIDS and tuberculosis (TB) have been more problematic, largely in that abnormally high numbers of antigen specific CD8+ T cells are required for protection. This study assessed the effect of temporarily dampening the chemokine receptor CXCR3 and CCR5 after vaccination on host immune responses by the administration of TAK-779, a small molecule CXCR3 and CCR5 antagonists commonly used to inhibit HIV infection. Our results showed that the use of TAK-779 enhanced memory CD8+ T cell immune responses both qualitatively and quantitatively. Treatment with TAK-779 following vaccination of an influenza virus antigen resulted in enhanced memory generation with more CD8+CD127+ memory precursor and fewer terminally differentiated effector CD8+CD69+ T cells. These memory T cells were able to become IFN-?-secreting effector cells when re-encountered the same antigen, which can further enhance the efficacy of vaccination. The mice vaccinated in the presence of TAK-779 were better protected upon influenza virus challenge than the control. These results showed that vaccination while temporarily inhibiting chemokine receptor CXCR3 and CCR5 by TAK-779 could be a promising strategy to generate large number of protective memory CD8+ T cells.

SUBMITTER: Li R

PROVIDER: S-EPMC5072403 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Temporary CXCR3 and CCR5 antagonism following vaccination enhances memory CD8 T cell immune responses.

Li Rui R Zhang Nan N Tian Miaomiao M Ran Zihan Z Zhu Mingjun M Zhu Haiyan H Han Fangting F Yin Juan J Zhong Jiang J

Molecular medicine (Cambridge, Mass.) 20160706

Although current vaccination strategies have been successful at preventing a variety of human diseases, attempts at vaccinating against some pathogens such as AIDS and tuberculosis (TB) have been more problematic, largely in that abnormally high numbers of antigen specific CD8+ T cells are required for protection. This study assessed the effect of temporarily dampening the chemokine receptor CXCR3 and CCR5 after vaccination on host immune responses by the administration of TAK-779, a small molec ...[more]

PMID: 27447731

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Project description:BACKGROUND:One of today's greatest hurdles for cancer immunotherapy is the absence of information regarding which tumor antigens are already recognized by patients receiving immunotherapies, and whether those therapies then boost or generate an immune response against tumor proteins. For CD8+ T cells in particular, patient-specific immune recognition and responses at the level of individual tumor antigens are rarely characterized. Because of this, some immunologists have turned to serum antibodies as an alternative measure of antigen-specific anti-tumor immunity. In this work, we sought to simultaneously interrogate serum IgG and CD8+ T cell recognition of individual tumor antigens to determine whether antigen-specific serum IgG antibodies provide a window into the behavior of antigen-specific CD8+ T cell responses. Using antibody-based assays to evaluate immune response repertoires and focus T cell antigen exploration could afford substantial advantages for discovering and monitoring the anti-cancer immune responses of patients enrolled on clinical trials. METHODS:We vaccinated female BALB/c mice with a novel combination of an autophagosome-enriched vaccine derived from 4T1 mammary carcinoma along with poly-I:C adjuvant, then screened serum for IgG binding to arrays of 15mer peptides containing known mutation sites in 4T1. Simultaneously, we primed CD8+ T cell cultures from these same animals with 8-11mer peptides derived from these antigens. These primed T cells were then stimulated to measure recognition of the peptides or live 4T1 cells by IFN? release. RESULTS:Vaccinated animals demonstrate increases in antigen-specific CD8+ T cell recognition of 4T1 tumor cells and peptides. For proteins confirmed in 4T1 cells and vaccine by mass spectrometry, there is a correlation between this increased CD8+ T cell IFN? release and serum IgG binding to individual peptide antigens. CONCLUSIONS:These results suggest it is possible to observe some features of a patient's antigen-specific T cell repertoire via an antibody surrogate, which has implications for tumor antigen discovery and clinical monitoring of antigen-specific anti-tumor immunity.

Dataset Information

Temporary CXCR3 and CCR5 antagonism following vaccination enhances memory CD8 T cell immune responses.

Publications

Temporary CXCR3 and CCR5 antagonism following vaccination enhances memory CD8 T cell immune responses.

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