Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun, Supranee; Pissani, Franco; Teigler, Jeffrey E.; Schultz, Bruce; Alter, Galit; Marovich, Mary; Robb, Merlin L.; Eller, Michael A.; Martin, Jeff; Deeks, Steven G.; Michael, Nelson L.; Streeck, Hendrik

doi:10.1128/jvi.00497-17

Cited by 31 publications

(20 citation statements)

References 29 publications

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“…Interestingly, the frequency of gut T FH cells correlated with the frequency of gut gp140-reactive memory B cells in cART-treated HIV-1-infected patients. In line with these results, it has been recently shown that HIV Env-specific CXCR5 + CD4 + T cells that secrete IL-21 are strongly associated with B cell memory phenotypes and function (55). The results suggested that circulating total and HIV-1-specific IL-21-producing T cells were more abundant with e-ART than with l-ART.…”

Section: Discussionsupporting

confidence: 67%

Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV-Specific B Cells in the Gut Mucosa of HIV-1–Infected Individuals

Planchais

Hocqueloux

Ibáñez

et al. 2018

The Journal of Immunology

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HIV-1 infection is associated with B cell dysregulation and dysfunction. In HIV-1-infected patients, we previously reported preservation of intestinal lymphoid structures and dendritic cell maturation pathways after early combination antiretroviral therapy (e-ART), started during the acute phase of the infection, compared with late combination antiretroviral therapy started during the chronic phase. In this study, we investigated whether the timing of combination antiretroviral therapy initiation was associated with the development of the HIV-1-specific humoral response in the gut. The results showed that e-ART was associated with higher frequencies of functional resting memory B cells in the gut. These frequencies correlated strongly with those of follicular Th cells in the gut. Importantly, frequencies of HIV-1 Env gp140-reactive B cells were higher in patients given e-ART, in whom gp140-reactive IgG production by mucosal B cells increased after stimulation. Moreover, IL-21 release by PBMCs stimulated with HIV-1 peptide pools was greater with e-ART than with late combination antiretroviral therapy. Thus, early treatment initiation helps to maintain HIV-1-reactive memory B cells in the gut as well as follicular Th cells, whose role is crucial in the development of potent affinity-matured and broadly neutralizing Abs.

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Section: Discussionsupporting

confidence: 67%

Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV-Specific B Cells in the Gut Mucosa of HIV-1–Infected Individuals

Planchais

Hocqueloux

Ibáñez

et al. 2018

The Journal of Immunology

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“…As CXCR5 is a key surface molecule expressed on Tfh cells, its expression has been used as an important marker of Tfh cells [17]. Therefore, we identified Tfh cells as CXCR5 expressing CD4+ T cells for identification of peripheral Tfh cells as described previously [17,32]. As CXCR5 expression was shown to be altered upon stimulation of T cells [17], the Tfh cells were identified ex vivo without any stimulation and the intracellular cytokine staining (ICS) for IL-21 was also carried out ex vivo without stimulation.…”

Section: Expansion Of Tfh Cells During Acute Dengue Illnessmentioning

confidence: 99%

Phenotype and functionality of follicular helper T cells in patients with acute dengue infection

et al. 2020

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Background: The association of functionality and phenotype of follicular helper T cells (Tfh) with dengue virus (DENV) specific antibody responses and clinical disease severity has not been well studied. Methods: We investigated the phenotype and functionality of Tfh cells and plasmablasts in adult patients (DF = 18, DHF = 22) with acute dengue (day 4 to 8 since onset of fever) of varying severity using multiparametric flowcytometry. The properties of Tfh cells were correlated with viraemia, disease severity, plasmablast responses and DENV-specific serum antibody responses. We further evaluated the kinetics of neutralizing antibodies (Neut50) throughout the course of illness in order to evaluate their association with clinical disease severity and viraemia. Results: Tfh cells (especially those producing IL-21 and co-expressing PD-1 and ICOS) were found to be significantly expanded (p < 0.0001) and highly activated in patients with DHF compared to those with DF. The frequency of Tfh cells significantly correlated with DENV-specific IgG, NS1-specific antibodies and Neut50 antibody titres in patients with DHF but not in those with DF. Although the Neut50 titres increased during the course of acute secondary DENV infection, they showed differences based on serotype. For instance, the Neut50 titres were significantly higher during the latter part of illness in patients with DF compared to DHF in DENV1 infection, while in DENV2, patients with DHF had significantly higher titres. The viral loads during early illness did not correlate with the subsequent rise in the Neut50 antibody titres during any time point of illness. Conclusions: The expansion of Tfh cells is associated with DHF and DENV-specific IgG, NS1-specific and neutralizing antibodies. Neut50 titres did not associate with disease severity or viraemia at the point of first presentation during the febrile phase, but later titres do show differential association with severity in patients with DENV1 compared to DENV2.

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“…Th1-dominated response and toward a more balanced profile composed of cytolytic and IL-21 ϩ CD4 T cells, the latter of which we previously identified as peripheral T follicular helper cells. Phenotypically, vaccination boosts did not lead to any significant increase in the Tfh cell-associated marker CXCR5, cMAF, or PD-1 (data not shown), indicating that phenotypic assessment of vaccine-induced Tfh cell responses is not sufficient for describing differences in the antigen-specific induced CD4 T cell populations (26). Among the responses induced by the four different prime and boost vaccination strategies, both ALVAC and ALVAC/bi-gp120 responses were dominated by CD40L (Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in Humans

Pissani

Schulte

Eller

et al. 2018

J Virol

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To date, six vaccine strategies have been evaluated in clinical trials for their efficacy at inducing protective immune responses against HIV infection. However, only the ALVAC-HIV/AIDSVAX B/E vaccine (RV144 trial) has demonstrated protection, albeit modestly (31%; = 0.03). One potential correlate of protection was a low-frequency HIV-specific CD4 T cell population with diverse functionality. Although CD4 T cells, particularly T follicular helper (Tfh) cells, are critical for effective antibody responses, most studies involving HIV vaccines have focused on humoral immunity or CD8 T cell effector responses, and little is known about the functionality and frequency of vaccine-induced CD4 T cells. We therefore assessed responses from several phase I/II clinical trials and compared them to responses to natural HIV-1 infection. We found that all vaccines induced a lower magnitude of HIV-specific CD4 T cell responses than that observed for chronic infection. Responses differed in functionality, with a CD40 ligand (CD40L)-dominated response and more Tfh cells after vaccination, whereas chronic HIV infection provoked tumor necrosis factor alpha (TNF-α)-dominated responses. The vaccine delivery route further impacted CD4 T cells, showing a stronger Th1 polarization after dendritic cell delivery than after intramuscular vaccination. In prime/boost regimens, the choice of prime and boost influenced the functional profile of CD4 T cells to induce more or less polyfunctionality. In summary, vaccine-induced CD4 T cell responses differ remarkably between vaccination strategies, modes of delivery, and boosts and do not resemble those induced by chronic HIV infection. Understanding the functional profiles of CD4 T cells that best facilitate protective antibody responses will be critical if CD4 T cell responses are to be considered a clinical trial go/no-go criterion. Only one HIV-1 candidate vaccine strategy has shown protection, albeit marginally (31%), against HIV-1 acquisition, and correlates of protection suggested that a multifunctional CD4 T cell immune response may be important for this protective effect. Therefore, the functional phenotypes of HIV-specific CD4 T cell responses induced by different phase I and phase II clinical trials were assessed to better show how different vaccine strategies influence the phenotype and function of HIV-specific CD4 T cell immune responses. The significance of this research lies in our comprehensive comparison of the compositions of the T cell immune responses to different HIV vaccine modalities. Specifically, our work allows for the evaluation of vaccination strategies in terms of their success at inducing Tfh cell populations.

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Cited by 31 publications

References 29 publications

Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV-Specific B Cells in the Gut Mucosa of HIV-1–Infected Individuals

Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV-Specific B Cells in the Gut Mucosa of HIV-1–Infected Individuals

Phenotype and functionality of follicular helper T cells in patients with acute dengue infection

Modulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in Humans

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