title: 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.
abstract: The inhibitory receptor programmed death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection; however, its role on CD4 T cells, specifically in the gut-associated lymphoid tissue, is less well understood. In this study, we show that a subset of CD4 T cells expresses high levels of PD-1 (PD-1(hi)) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1(hi) CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1(hi) cells (as a percentage of CD4 T cells) dramatically increased in the rectal mucosa; however, a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1(hi) cells expressed CCR5, and despite this low level of viral coreceptor expression, a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1(hi) CD4 T cell enrichment, and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B(+) CD8 T cells within the lymphoid tissue, suggesting a role for antiviral CD8 T cells in limiting aberrant expansion of PD-1(hi) CD4 T cells. These results highlight the importance of developing vaccines that enhance antiviral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV(+)PD-1(hi) CD4 T cells at mucosal sites as a means to enhance viral control.
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Geetha H
authors.initials: GH
authors.lastname: Mylvaganam
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Jung-Joo
authors.initials: JJ
authors.lastname: Hong
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Shanmugalakshmi
authors.initials: S
authors.lastname: Sadagopal
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Suefen
authors.initials: S
authors.lastname: Kwa
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Rahul
authors.initials: R
authors.lastname: Basu
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and.
authors.forename: Benton
authors.initials: B
authors.lastname: Lawson
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; and ramara@emory.edu.
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival; D015870:Gene Expression; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta; D010581:Peyer's Patches / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism; D012007:Rectum / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000954:Antigens, Surface; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; D019713:Receptors, CCR5; D054380:Receptors, CXCR5