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

Vijayakumar Velu, Geetha Hanna Mylvaganam, Sailaja Gangadhara, Jung Joo Hong, Smita Iyer, Sanjeev Gumber, Chris C. Ibegbu, Francois Villinger, Rama Rao Amara

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4+ cells did not change, and CCR6+ cells decreased. CXCR3+, but not CXCR32, GC Tfh cells produced IFN-g (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4+IFN-g+ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3+ GC Tfh cells also expressed higher levels of ICOS, CCR5, and a4b7 and contained more copies of SIV DNA compared with CXCR32 GC Tfh cells. However, CXCR3+ and CXCR32 GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs.

Original languageEnglish (US)
Pages (from-to)1832-1842
Number of pages11
JournalJournal of Immunology
Volume197
Issue number5
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Simian Immunodeficiency Virus
Germinal Center
Lymphoid Tissue
Virus Diseases
Helper-Inducer T-Lymphocytes
Infection
Macaca mulatta
HIV Infections
Cytokines
Hypergammaglobulinemia
CD40 Ligand
Chemokine Receptors
B-Lymphocytes
Immunoglobulin G

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja; Hong, Jung Joo; Iyer, Smita; Gumber, Sanjeev; Ibegbu, Chris C.; Villinger, Francois; Amara, Rama Rao.

In: Journal of Immunology, Vol. 197, No. 5, 01.09.2016, p. 1832-1842.

Research output: Contribution to journalArticle

Velu, Vijayakumar ; Mylvaganam, Geetha Hanna ; Gangadhara, Sailaja ; Hong, Jung Joo ; Iyer, Smita ; Gumber, Sanjeev ; Ibegbu, Chris C. ; Villinger, Francois ; Amara, Rama Rao. / 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. In: Journal of Immunology. 2016 ; Vol. 197, No. 5. pp. 1832-1842.
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abstract = "Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4+ cells did not change, and CCR6+ cells decreased. CXCR3+, but not CXCR32, GC Tfh cells produced IFN-g (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4+IFN-g+ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3+ GC Tfh cells also expressed higher levels of ICOS, CCR5, and a4b7 and contained more copies of SIV DNA compared with CXCR32 GC Tfh cells. However, CXCR3+ and CXCR32 GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs.",
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AU - Iyer, Smita

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