Accumulation of follicular CD8+ T cells in pathogenic SIV infection
Sara Ferrando-Martinez, … , Constantinos Petrovas, Richard A. Koup
Sara Ferrando-Martinez, … , Constantinos Petrovas, Richard A. Koup
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2089-2103. https://doi.org/10.1172/JCI96207.
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Research Article AIDS/HIV Immunology

Accumulation of follicular CD8+ T cells in pathogenic SIV infection

Abstract

LN follicles constitute major reservoir sites for HIV/SIV persistence. Cure strategies could benefit from the characterization of CD8+ T cells able to access and eliminate HIV-infected cells from these areas. In this study, we provide a comprehensive analysis of the phenotype, frequency, localization, and functionality of follicular CD8+ T cells (fCD8+) in SIV-infected nonhuman primates. Although disorganization of follicles was a major factor, significant accumulation of fCD8+ cells during chronic SIV infection was also observed in intact follicles, but only in pathogenic SIV infection. In line with this, tissue inflammatory mediators were strongly associated with the accumulation of fCD8+ cells, pointing to tissue inflammation as a major factor in this process. These fCD8+ cells have cytolytic potential and can be redirected to target and kill HIV-infected cells using bispecific antibodies. Altogether, our data support the use of SIV infection to better understand the dynamics of fCD8+ cells and to develop bispecific antibodies as a strategy for virus eradication.

Authors

Sara Ferrando-Martinez, Eirini Moysi, Amarendra Pegu, Sarah Andrews, Krystelle Nganou Makamdop, David Ambrozak, Adrian B. McDermott, David Palesch, Mirko Paiardini, George N. Pavlakis, Jason M. Brenchley, Daniel Douek, John R. Mascola, Constantinos Petrovas, Richard A. Koup

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Figure 1

fCD8+ T cells accumulate in LNs during chronic SIV infection.

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fCD8+ T cells accumulate in LNs during chronic SIV infection. (A) Gating...
(A) Gating strategy for CCR7loCD95hiCXCR5hi fCD8+ cells. (B) Flow cytometric pooled data showing the relative frequency of fCD8+ T cells in noninfected (n = 16 SIV–), acute SIV+ (day 14, n = 10), early chronic SIV+ (day 45, n = 8), and chronic SIV+ (>6 months, n = 17) RMs. *P < 0.05 and ***P < 0.0001, by Mann-Whitney U test. (C) Representative example of histocytometric analysis of follicular cells from 1 chronically SIV-infected animal (7 different samples were analyzed using this method). GCs were defined by CD20+Ki67+ coexpression, and CD4+ (CD3+CD4+) and CD8+ (CD3+CD4–) T cells were quantified within each GC. A representative confocal image and its reconstruction using histocytometry are shown. Scale bar: 400 μm. (D) Histocytometric pooled data showing the relative frequency and actual numbers (per μm2) of CD8+ T cells within GCs. Each point represents an individual GC. Different symbols represent different samples (n = 2 SIV–; n = 2 acute SIV+, n = 3 chronic SIV+). **P < 0.001 and ***P < 0.0001, by Mann-Whitney U test. (E) Pooled data showing the relative frequency and actual numbers (per μm2) of CD8+ T cells within intact and disorganized GCs from chronically SIV-infected animals (n = 5). Data from SIV– (n = 2) and acute SIV-infected animals (n = 2) are also shown. Each point represents an individual GC, and different symbols represent different LN samples. **P < 0.001 and ***P < 0.0001, by Mann-Whitney U test.