TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1

Allam, Atef; Majji, Sai; Peachman, Kristina K.; Jagodzinski, Linda L.; Kim, Jiae; Ratto‐Kim, Silvia; Wijayalath, Wathsala; Merbah, Mélanie; Kim, Jerome H.; Michael, Nelson L.; Alving, Carl R.; Casares, Sofía; Rao, Mangala

doi:10.1038/srep10443

Cited by 43 publications

(49 citation statements)

References 71 publications

(105 reference statements)

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“…Moreover, the data presented here demonstrate a marked expansion of these CXCR3 + GC-Tfh cells during SIV infection. Similar findings were reported in the blood of HIV infected individuals as well as mouse model of HIV infection where CXCR3 + CD4 T cells preferentially expressed the HIV-co-receptor CCR5 (45, 51). Hence, we speculate that CXCR3 + CCR5 + α4β7 + GC-Tfh subsets may have the capacity to maintain a dynamic viral reservoir in GCs under anti-retroviral therapy.…”

Section: Discussionsupporting

confidence: 84%

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

Mylvaganam

Gangadhara

et al. 2016

The Journal of Immunology

124

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Chronic HIV infection is associated with accumulation of germinal center T follicular helper cells (GC-Tfh) 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 antibody production during chronic SIV/HIV infection is not known. To address this, here we characterized the expression of CXCR3, CCR4, and CCR6 on GC-Tfh in lymph nodes following SIVmac251 infection in rhesus macaques (RMs). In SIV naïve RM, only a small fraction of GC-Tfh expressed CXCR3, CCR4 and CCR6. However, during chronic SIV infection, the majority of GC-Tfh cells expressed CXCR3, while the proportion of CCR4+ cells did not change and CCR6+ cells decreased. CXCR3+ but not CXCR3− GC-Tfh produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine) while both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4+ IFN-γ+ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3+ GC-Tfh also expressed higher levels of ICOS, CCR5 and α4β7, contained more copies of SIV DNA compared to CXCR3− GC-Tfh cells. However, both CXCR3+ and CXCR3− GC-Tfh 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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Section: Discussionsupporting

confidence: 84%

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

Mylvaganam

Gangadhara

et al. 2016

The Journal of Immunology

124

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“…It is also possible that infected T h 17 cells directly become T fh cells (32,33), which would then be capable of migration to secondary lymphoid tissues (Fig. 7), where they are capable of replication at high levels, despite their low expression of CCR5 (68,69). Our findings may aid in therapeutic intervention strategies aimed at preventing viral production during acute HIV infection or reducing the size of the viral reservoir in people living with HIV.…”

Section: Discussionmentioning

confidence: 94%

Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

Christensen-Quick

Lafferty

Sun

et al. 2016

J Virol

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Human immunodeficiency virus (HIV) infects and depletes CD4 IMPORTANCE Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T h 17 cells and HIV replication. T h 17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4؉ T cell subsets that share several requirements for their differentiation: T h 17 and T fh cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.

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“…The heightened permissivity of tonsillar T FH cannot be fully explained by differences in memory subsets, cellular activation, or chemokine co-receptor expression [9]. Importantly, in an HIV-model system using humanized mice, T FH rapidly accumulate in gut and female reproductive tract mucosal tissues and are the most permissive CD4+ T cell subset to HIV [10], suggesting that gut and vaginal T FH may play a key role in establishment of HIV infection as well as ongoing virus replication.…”

Section: Role Of Tfh In Hiv Replication In Untreated Diseasementioning

confidence: 99%

T FH in HIV Latency and as Sources of Replication-Competent Virus

Brodie

Connick

2016

Trends in Microbiology

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During untreated disease, HIV replication is concentrated within T follicular helper cells (TFH). Heightened permissiveness, the presence of highly infectious virions on follicular dendritic cells (FDC), low frequencies of virus-specific cytotoxic T lymphocytes (CTL) in B cell follicles, expansions in TFH, and TFH dysfunction all likely promote replication in TFH. Limited data suggest that memory TFH play a role in the latent or subclinical reservoir of HIV during antiretroviral therapy (ART), potentially for many of the same reasons. A better understanding of the role of memory TFH and FDC-bound virions in promoting recrudescent viremia in the setting of ART cessation is essential. Studies that target follicular virus reservoirs are needed to determine their role in HIV latency and to suggest successful cure strategies.

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TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1

Cited by 43 publications

References 71 publications

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

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

Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

T FH in HIV Latency and as Sources of Replication-Competent Virus

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TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1

Cited by 43 publications

References 71 publications

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

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

Human T h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

T FH in HIV Latency and as Sources of Replication-Competent Virus

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Product

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Human T _h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection