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

Prossy Naluyima, Kerri G. Lal, Margaret C. Costanzo, Gustavo H. Kijak, Veronica D. Gonzalez, Kim Blom, Leigh Anne Eller, Matthew Creegan, Ting Hong, Dohoon Kim, Thomas C. Quinn, Niklas K. Björkström, Hans Gustaf Ljunggren, David Serwadda, Elly T. Katabira, Nelson K. Sewankambo, Ronald H. Gray, Jared M. Baeten, Nelson L. Michael, Fred Wabwire-MangenMerlin L. Robb, Diane L. Bolton, Johan K. Sandberg, Michael A. Eller

Research output: Contribution to journalArticle

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 FcγRIIIA (CD16). The FcγRIIIA+ 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-7Rα- surface phenotype with high expression of the Helios transcription factor. Interestingly, the FcγRIIIA+ CD8 T cells mediated HIV-specific Ab-dependent cellular cytotoxicity (ADCC) activity at levels comparable with NK cells on a per cell basis. The FcγRIIIA+ 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 FcγRIIIA+ 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 HIVspecific ADCC is a function CD8 T cells use to target HIV-infected cells. Furthermore, as the FcγRIIIA+ CD8 T cells persist in treatment, they contribute significantly to the ADCC-capable effector cell pool in patients on antiretroviral therapy.

Original languageEnglish (US)
Pages (from-to)2210-2221
Number of pages12
JournalJournal of Immunology
Volume203
Issue number8
DOIs
StatePublished - Oct 15 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Naluyima, P., Lal, K. G., Costanzo, M. C., Kijak, G. H., Gonzalez, V. D., Blom, K., Eller, L. A., Creegan, M., Hong, T., Kim, D., Quinn, T. C., Björkström, N. K., Ljunggren, H. G., Serwadda, D., Katabira, E. T., Sewankambo, N. K., Gray, R. H., Baeten, J. M., Michael, N. L., ... Eller, M. A. (2019). 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. Journal of Immunology, 203(8), 2210-2221. https://doi.org/10.4049/jimmunol.1900422