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CD8⁺ memory T-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naive T-cell anergy.

ABSTRACT: Whether inflation of CD8⁺ memory T (mT) cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late CD8⁺ T-cell immunity is a long-standing paradox. We have previously established an animal model with mT-cell inflation by transferring ConA-stimulated monoclonal CD8⁺ T cells derived from Ova-specific T-cell-receptor transgenic OTI mice into irradiation-induced lymphopenic B6 mice. In this study, we also established another two animal models with mT-cell inflation by transferring, 1) ConA-stimulated monoclonal CD8⁺ T cells derived from lymphocytic choriomeningitis virus glycoprotein-specific T-cell-receptor transgenic P14 mice, and 2) ConA-stimulated polyclonal CD8⁺ T cells derived from B6.1 mice into B6 mice with irradiation-induced lymphopenia. We vaccinated these mice with recombinant Ova-expressing Listeria monocytogenes and Ova-pulsed dendritic cells, which stimulated CD4⁺ T cell-independent and CD4⁺ T-cell-dependent CD8⁺ T-cell responses, respectively, and assessed Ova-specific CD8⁺ T-cell responses by flow cytometry. We found that Ova-specific CD8⁺ T-cell responses derived from the latter but not the former vaccination were significantly reduced in mice with CD8⁺ mT-cell inflation compared to wild-type B6 mice. We determined that naïve CD8⁺ T cells purified from splenocytes of mice with mT-cell inflation had defects in cell proliferation upon stimulation in vitro and in vivo and upregulated T-cell anergy-associated Itch and GRAIL molecules. Taken together, our data reveal that CD8⁺ mT-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naïve T-cell anergy, and thus show promise for the design of efficient vaccines for elderly patients with CD8⁺ mT-cell inflation.

SUBMITTER: Xu A

PROVIDER: S-EPMC5479263 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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CD8+ memory T-cell inflation renders compromised CD4+ T-cell-dependent CD8+ T-cell immunity via naïve T-cell anergy.

Xu Aizhang A Freywald Andrew A Xie Yufeng Y Li Zejun Z Xiang Jim J

ImmunoTargets and therapy 20170615

Whether inflation of CD8+ memory T (mT) cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late CD8+ T-cell immunity is a long-standing paradox. We have previously established an animal model with mT-cell inflation by transferring ConA-stimulated monoclonal CD8+ T cells derived from Ova-specific T-cell-receptor transgenic OTI mice into irradiation-induced lymphopenic B6 mice. In this study ...[more]

PMID: 28670575

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Project description:Treatment with anti-CD20, used in many diseases in which B cells play a pathogenic role, has been associated with susceptibility to intracellular infections. Here, we studied the effect of anti-CD20 injection on CD8+ T cell immunity using an experimental model of Trypanosoma cruzi infection, in which CD8+ T cells play a pivotal role. C57BL/6 mice were treated with anti-CD20 for B cell depletion prior to T. cruzi infection. Infected anti-CD20-treated mice exhibited a CD8+ T cell response with a conserved expansion phase followed by an early contraction, resulting in a strong reduction in total and parasite-specific CD8+ T cell numbers at 20 days postinfection. Anti-CD20 injection increased the frequency of apoptotic CD8+ T cells, decreased the number of effector and memory CD8+ T cells, and reduced the frequency of proliferating and cytokine-producing CD8+ T cells. Accordingly, infected anti-CD20-treated mice presented lower cytotoxicity of T. cruzi peptide-pulsed target cells in vivo All of these alterations in CD8+ T cell immunity were associated with increased tissue parasitism. Anti-CD20 injection also dampened the CD8+ T cell response, when this had already been generated, indicating that B cells were involved in the maintenance rather than the induction of CD8+ T cell immunity. Anti-CD20 injection also resulted in a marked reduction in the frequency of interleukin-6 (IL-6)- and IL-17A-producing cells, and recombinant IL-17A (rIL-17A) injection partially restored the CD8+ T cell response in infected anti-CD20-treated mice. Thus, anti-CD20 reduced CD8+ T cell immunity, and IL-17A is a candidate for rescuing deficient responses either directly or indirectly.IMPORTANCE Monoclonal antibody targeting the CD20 antigen on B cells is used to treat the majority of non-Hodgkin lymphoma patients and some autoimmune disorders. This therapy generates adverse effects, notably opportunistic infections and activation of viruses from latency. Here, using the infection murine model with the intracellular parasite Trypanosoma cruzi, we report that anti-CD20 treatment affects not only B cell responses but also CD8+ T cell responses, representing the most important immune effectors involved in control of intracellular pathogens. Anti-CD20 treatment, directly or indirectly, affects cytotoxic T cell number and function, and this deficient response was rescued by the cytokine IL-17A. The identification of IL-17A as the cytokine capable of reversing the poor response of CD8+ T cells provides information about a potential therapeutic treatment aimed at enhancing defective immunity induced by B cell depletion.

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CD8⁺ memory T-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naive T-cell anergy.

Publications

CD8<sup>+</sup> memory T-cell inflation renders compromised CD4<sup>+</sup> T-cell-dependent CD8<sup>+</sup> T-cell immunity via naïve T-cell anergy.

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Dataset Information

CD8+ memory T-cell inflation renders compromised CD4+ T-cell-dependent CD8+ T-cell immunity via naive T-cell anergy.

Publications

CD8<sup>+</sup> memory T-cell inflation renders compromised CD4<sup>+</sup> T-cell-dependent CD8<sup>+</sup> T-cell immunity via naïve T-cell anergy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD8⁺ memory T-cell inflation renders compromised CD4⁺ T-cell-dependent CD8⁺ T-cell immunity via naive T-cell anergy.