Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

Contributed by Rafi Ahmed, December 29, 2016 (sent for review December 18, 2016; reviewed by Barbara K. Felber and Savita Pahwa)
February 3, 2017
114 (8) 1976-1981

Significance

Simian immunodeficiency virus (SIV)-specific follicular CD8 T cells represent a unique subset of antiviral CD8 T cells that rapidly expand during pathogenic SIV infection, localize within B-cell follicles, and contribute to control of chronic SIV replication. The potential for these cells to infiltrate sites of ongoing viral replication and viral persistence and the ability to induce these cells by vaccination provide a tremendous opportunity to develop and optimize therapeutic strategies to target and reduce the HIV reservoirs in lymphoid tissues.

Abstract

A significant challenge to HIV eradication is the elimination of viral reservoirs in germinal center (GC) T follicular helper (Tfh) cells. However, GCs are considered to be immune privileged for antiviral CD8 T cells. Here, we show a population of simian immunodeficiency virus (SIV)-specific CD8 T cells express CXCR5 (C-X-C chemokine receptor type 5, a chemokine receptor required for homing to GCs) and expand in lymph nodes (LNs) following pathogenic SIV infection in a cohort of vaccinated macaques. This expansion was greater in animals that exhibited superior control of SIV. The CXCR5+ SIV-specific CD8 T cells demonstrated enhanced polyfunctionality, restricted expansion of antigen-pulsed Tfh cells in vitro, and possessed a unique gene expression pattern related to Tfh and Th2 cells. The increase in CXCR5+ CD8 T cells was associated with the presence of higher frequencies of SIV-specific CD8 T cells in the GC. Following TCR-driven stimulation in vitro, CXCR5+ but not CXCR5– CD8 T cells generated both CXCR5+ as well as CXCR5– cells. However, the addition of TGF-β to CXCR5– CD8 T cells induced a population of CXCR5+ CD8 T cells, suggesting that this cytokine may be important in modulating these CXCR5+ CD8 T cells in vivo. Thus, CXCR5+ CD8 T cells represent a unique subset of antiviral CD8 T cells that expand in LNs during chronic SIV infection and may play a significant role in the control of pathogenic SIV infection.

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Data Availability

Data deposition: Microarray results have been deposited in the Gene Expression Omnibus database, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=epmdikuulfmbhmj&acc=GSE74751 (accession no. GSE74751).

Acknowledgments

We thank the Yerkes Division of Research Resources and veterinary staff for animal care and procedures, the Emory Flow Cytometry core for cell sorting, Emory Center For Aids Research Virology Core for VL assays, and the NIH AIDS Research and Reference Reagent Program for the provision of peptides. This work was supported by National Institutes of Health Grants R36 AI112787, P01 AI88575, and U19 AI109633 (to R.R.A.) and AI096966 (to P.J.S.); Yerkes National Primate Research Center Base Grant P51 RR00165; and Emory Center for AIDS Research Grant P30 AI050409.

Supporting Information

Supporting Information (PDF)

References

1
T Matano, et al., Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72, 164–169 (1998).
2
JE Schmitz, et al., Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).
3
X Jin, et al., Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189, 991–998 (1999).
4
P Borrow, H Lewicki, BH Hahn, GM Shaw, MB Oldstone, Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68, 6103–6110 (1994).
5
SA Migueles, et al., HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3, 1061–1068 (2002).
6
MR Betts, et al., HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).
7
RA Koup, et al., Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68, 4650–4655 (1994).
8
ZM Ndhlovu, et al., Magnitude and kinetics of CD8+ T cell activation during hyperacute HIV infection impact viral set point. Immunity 43, 591–604 (2015).
9
DH Barouch, et al., Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 486–492 (2000).
10
RR Amara, et al., Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74 (2001).
11
J Liu, et al., Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457, 87–91 (2009).
12
SG Hansen, et al., Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011).
13
G Pantaleo, et al., Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci USA 88, 9838–9842 (1991).
14
M Perreau, et al., Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med 210, 143–156 (2013).
15
GH Mylvaganam, et al., Diminished viral control during simian immunodeficiency virus infection is associated with aberrant PD-1hi CD4 T cell enrichment in the lymphoid follicles of the rectal mucosa. J Immunol 193, 4527–4536 (2014).
16
E Connick, et al., CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol 178, 6975–6983 (2007).
17
E Connick, et al., Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J Immunol 193, 5613–5625 (2014).
18
Y Fukazawa, et al., B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med 21, 132–139 (2015).
19
R Förster, et al., A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).
20
D Breitfeld, et al., Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192, 1545–1552 (2000).
21
YA Leong, et al., CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol 17, 1187–1196 (2016).
22
R He, et al., Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–428 (2016).
23
SJ Im, et al., Defining CD8(+) T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).
24
C Petrovas, et al., CD4 T follicular helper cell dynamics during SIV infection. J Clin Invest 122, 3281–3294 (2012).
25
M Lindqvist, et al., Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 122, 3271–3280 (2012).
26
JJ Hong, PK Amancha, K Rogers, AA Ansari, F Villinger, Spatial alterations between CD4(+) T follicular helper, B, and CD8(+) T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J Immunol 188, 3247–3256 (2012).
27
V Velu, et al., Induction of Th1-biased T follicular helper (Tfh) cells in lymphoid tissues during chronic simian immunodeficiency virus infection defines functionally distinct germinal center Tfh cells. J Immunol 197, 1832–1842 (2016).
28
MF Quigley, VD Gonzalez, A Granath, J Andersson, JK Sandberg, CXCR5+ CCR7- CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles. Eur J Immunol 37, 3352–3362 (2007).
29
S Kannanganat, et al., Human immunodeficiency virus type 1 controllers but not noncontrollers maintain CD4 T cells coexpressing three cytokines. J Virol 81, 12071–12076 (2007).
30
K Yoshida, et al., Bcl6 controls granzyme B expression in effector CD8+ T cells. Eur J Immunol 36, 3146–3156 (2006).
31
CY Yang, et al., The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 12, 1221–1229 (2011).
32
N Schmitt, et al., The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol 15, 856–865 (2014).
33
MJ Ploquin, et al., Distinct expression profiles of TGF-beta1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections. Retrovirology 3, 37 (2006).
34
G Poli, et al., Transforming growth factor beta suppresses human immunodeficiency virus expression and replication in infected cells of the monocyte/macrophage lineage. J Exp Med 173, 589–597 (1991).
35
; Committee on Care and Use of Laboratory Animals, Guide for the Care and Use of Laboratory Animals (Natl Inst Health, Bethesda), DHHS Publ No (NIH) 85-23. (1996).
36
S Kwa, et al., CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus (SIV) vaccine enhances protection against neutralization-resistant mucosal SIV infection. J Virol 89, 4690–4695 (2015).
37
V Velu, et al., Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).
38
HM Abdelaal, et al., Comparison of Vibratome and Compresstome sectioning of fresh primate lymphoid and genital tissues for in situ MHC-tetramer and immunofluorescence staining. Biol Proced Online 17, 2 (2015).
39
C Kline, et al., Persistence of viral reservoirs in multiple tissues after antiretroviral therapy suppression in a macaque RT-SHIV model. PLoS One 8, e84275 (2013).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 114 | No. 8
February 21, 2017
PubMed: 28159893

Classifications

Data Availability

Data deposition: Microarray results have been deposited in the Gene Expression Omnibus database, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=epmdikuulfmbhmj&acc=GSE74751 (accession no. GSE74751).

Submission history

Published online: February 3, 2017
Published in issue: February 21, 2017

Keywords

  1. SIV
  2. follicular CD8 T cells
  3. CXCR5+CD8+ T cells
  4. lymphoid follicles
  5. HIV

Acknowledgments

We thank the Yerkes Division of Research Resources and veterinary staff for animal care and procedures, the Emory Flow Cytometry core for cell sorting, Emory Center For Aids Research Virology Core for VL assays, and the NIH AIDS Research and Reference Reagent Program for the provision of peptides. This work was supported by National Institutes of Health Grants R36 AI112787, P01 AI88575, and U19 AI109633 (to R.R.A.) and AI096966 (to P.J.S.); Yerkes National Primate Research Center Base Grant P51 RR00165; and Emory Center for AIDS Research Grant P30 AI050409.

Authors

Affiliations

Geetha H. Mylvaganam
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Daniel Rios
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322;
Hadia M. Abdelaal
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108;
Department of Microbiology and Immunology, Zagazig University, Zagazig, Egypt 44519;
Smita Iyer
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Gregory Tharp
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Maud Mavigner
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322
Sakeenah Hicks
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Ann Chahroudi
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Steven E. Bosinger
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Ifor R. Williams
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322;
Pamela J. Skinner
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108;
Vijayakumar Velu1 [email protected]
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;

Notes

1
To whom correspondence may be addressed. Email: [email protected], [email protected], or [email protected].
Author contributions: G.H.M., R.A., I.R.W., P.J.S., V.V., and R.R.A. designed research; G.H.M., D.R., H.M.A., G.T., M.M., S.H., and V.V. performed research; S.I. contributed new reagents/analytic tools; G.H.M., D.R., H.M.A., G.T., M.M., A.C., S.E.B., I.R.W., P.J.S., V.V., and R.R.A. analyzed data; and G.H.M., R.A., V.V., and R.R.A. wrote the paper.
Reviewers: B.K.F., National Cancer Institute; and S.P., University of Miami, Miller School of Medicine.

Competing Interests

Conflict of interest statement: R.R.A. is a coinventor of DNA/MVA vaccine technology, and Emory University licensed this technology to Geovax Inc.

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    Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection
    Proceedings of the National Academy of Sciences
    • Vol. 114
    • No. 8
    • pp. 1739-E1574

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