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Terminal Effector CD8 T Cells Defined by an IKZF2⁺IL-7R^- Transcriptional Signature Express Fc?RIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

ABSTRACT: HIV-1 infection expands large populations of late-stage differentiated CD8 T cells that may persist long after viral escape from TCR recognition. In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA⁺CD57⁺ terminal effector CD8 T cells expressing Fc?RIIIA (CD16). The Fc?RIIIA⁺ CD8 T cells displayed a distinctive transcriptional profile between conventional CD8 T cells and NK cells, characterized by high levels of IKZF2 and low expression of IL7R This transcriptional profile translated into a distinct NKp80⁺ IL-7R?^- surface phenotype with high expression of the Helios transcription factor. Interestingly, the Fc?RIIIA⁺ CD8 T cells mediated HIV-specific Ab-dependent cellular cytotoxicity (ADCC) activity at levels comparable with NK cells on a per cell basis. The Fc?RIIIA⁺ CD8 T cells were highly activated in a manner that correlated positively with expansion of the CD8 T cell compartment and with plasma levels of soluble mediators of antiviral immunity and inflammation such as IP-10, TNF, IL-6, and TNFRII. The frequency of Fc?RIIIA⁺ CD8 T cells persisted as patients initiated suppressive antiretroviral therapy, although their activation levels declined. These data indicate that terminally differentiated effector CD8 T cells acquire enhanced innate cell-like characteristics during chronic viral infection and suggest that HIV-specific ADCC is a function CD8 T cells use to target HIV-infected cells. Furthermore, as the Fc?RIIIA⁺ CD8 T cells persist in treatment, they contribute significantly to the ADCC-capable effector cell pool in patients on antiretroviral therapy.

SUBMITTER: Naluyima P

PROVIDER: S-EPMC6778306 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Terminal Effector CD8 T Cells Defined by an IKZF2+IL-7R- Transcriptional Signature Express FcγRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

Naluyima Prossy P Lal Kerri G KG Costanzo Margaret C MC Kijak Gustavo H GH Gonzalez Veronica D VD Blom Kim K Eller Leigh Anne LA Creegan Matthew M Hong Ting T Kim Dohoon D Quinn Thomas C TC Björkström Niklas K NK Ljunggren Hans-Gustaf HG Serwadda David D Katabira Elly T ET Sewankambo Nelson K NK Gray Ronald H RH Baeten Jared M JM Michael Nelson L NL Wabwire-Mangen Fred F Robb Merlin L ML Bolton Diane L DL Sandberg Johan K JK Eller Michael A MA

Journal of immunology (Baltimore, Md. : 1950) 20190913 8

HIV-1 infection expands large populations of late-stage differentiated CD8 T cells that may persist long after viral escape from TCR recognition. In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA+CD57+ terminal effector CD8 T cells expressing FcγRIIIA (CD16). The FcγRIIIA+ CD8 T cells displayed a di ...[more]

PMID: 31519862

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Project description:BackgroundTh cells (helper T cells) have multiple functions in Schistosoma japonicum (S. japonicum) infection. Inducible co-stimulator (ICOS) is induced and expressed in activated T lymphocytes, which enhances the development of B cells and antibody production through the ICOS/ICOSL pathway. It remains unclear about the role and possible regulating mechanism of ICOS+ Th cells in the spleen of S. japonicum-infected C57BL/6 mice.MethodsC57BL/6 mice were infected with cercariae of S. japonicum through the abdomen. The expression of ICOS, activation markers, and the cytokine production on CD4+ ICOS+ Th cells were detected by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Moreover, the differentially expressed gene data of ICOS+ and ICOS- Th cells from the spleen of infected mice were obtained by mRNA sequencing. Besides, Western blot and chromatin immunoprecipitation (ChIP) were used to explore the role of Ikzf2 on ICOS expression.ResultsAfter S. japonicum infection, the expression of ICOS molecules gradually increased in splenic lymphocytes, especially in Th cells (P < 0.01). Compared with ICOS- Th cells, more ICOS+ Th cells expressed CD69, CD25, CXCR5, and CD40L (P < 0.05), while less of them expressed CD62L (P < 0.05). Also, ICOS+ Th cells expressed more cytokines, such as IFN-γ, IL-4, IL-10, IL-2, and IL-21 (P < 0.05). RNA sequencing results showed that many transcription factors were increased significantly in ICOS+ Th cells, especially Ikzf2 (P < 0.05). And then, the expression of Ikzf2 was verified to be significantly increased and mainly located in the nuclear of ICOS+ Th cells. Finally, ChIP experiments and dual-luciferase reporter assay confirmed that Ikzf2 could directly bind to the ICOS promoter in Th cells.ConclusionIn this study, ICOS+ Th cells were found to play an important role in S. japonicum infection to induce immune response in the spleen of C57BL/6 mice. Additionally, Ikzf2 was found to be one important transcription factor that could regulate the expression of ICOS in the spleen of S. japonicum-infected C57BL/6 mice.

Dataset Information

Terminal Effector CD8 T Cells Defined by an IKZF2⁺IL-7R^- Transcriptional Signature Express Fc?RIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

Publications

Terminal Effector CD8 T Cells Defined by an IKZF2<sup>+</sup>IL-7R<sup>-</sup> Transcriptional Signature Express FcγRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Terminal Effector CD8 T Cells Defined by an IKZF2+IL-7R- Transcriptional Signature Express Fc?RIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

Publications

Terminal Effector CD8 T Cells Defined by an IKZF2<sup>+</sup>IL-7R<sup>-</sup> Transcriptional Signature Express FcγRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Terminal Effector CD8 T Cells Defined by an IKZF2⁺IL-7R^- Transcriptional Signature Express Fc?RIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.