Induction of ICOS
 +
 CXCR3
 +
 CXCR5
 +
 T
 H
 Cells Correlates with Antibody Responses to Influenza Vaccination

Bentebibel, Salah Eddine; Lopez, Santiago M C; Obermoser, Gerlinde; Schmitt, Nathalie; Mueller, Cynthia; Harrod, Carson; Flaño, Emilio; Mejías, Asunción; Albrecht, Randy A.; Blankenship, Derek; Xu, Hui; Pascual, Virginia; Banchereau, Jacques; García‐Sastre, Adolfo; Palucka, A. Karolina; Ramilo, Octavio; Ueno, Hideki

doi:10.1126/scitranslmed.3005191

Cited by 539 publications

(632 citation statements)

References 45 publications

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“…T FH cells were first described in human blood and tonsils as CD4 + T-cells expressing CXCR5, a chemokine receptor that is required for homing to the B-cell follicles (Förster et al, 1994;Breitfeld et al, 2000;Schaerli et al, 2000;Kim et al, 2001). However, unlike GC T FH cells, blood memory T FH cells (Schmitt et al, 2014) do not express Bcl-6 protein, a T FH -associated transcription factor, thus indicating that Bcl-6 is dispensable for maintenance of these cells (Bentebibel et al, 2013;He et al, 2013).…”

Section: Follicular Helper T-cells (T Fhmentioning

confidence: 99%

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Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Bruno

Fornara

Zelini

et al. 2016

Journal of General Virology

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Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-g + ) CD4 + and CD8 + T-cells. Circulating CXCR5 + CD4 + (memory T follicular helper -T FH -cells) were identified as activated T FH (ICOS + PD-1 ++ CCR7 lo ) and quiescent cells. In the early stages of primary infection, activated T FH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4 + T-cells, HCMV clearance and progressive reduction in activated T FH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated T FH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated T FH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of T FH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

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Section: Follicular Helper T-cells (T Fhmentioning

confidence: 99%

“…Finally, blood memory T FH 1 cells may help memory B-cell differentiation into plasma cells via secretion of IL-21 and IL-10 but only when they become ICOS + PD-1 ++ CCR7 lo activated cells (Bentebibel et al, 2013).…”

Section: Follicular Helper T-cells (T Fhmentioning

confidence: 99%

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Bruno

Fornara

Zelini

et al. 2016

Journal of General Virology

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“…In a small number of individuals for whom cryopreserved PBMCs were available, we evaluated the frequency of activated ICOS + PD1 +++ CXCR5 + CD4 T cells after vaccination. ICOS + PD1 +++ CXCR5 + CD4 T cells are found in the blood of individuals with ongoing immune responses and may be a subpopulation of Tfh cells trafficking through the blood before becoming GC Tfh cells (8,22,39,40). Even with only six individuals available for analysis, plasma CXCL13 concentration responses correlated with the increase in activated ICOS + PD1 +++ CXCR5 + CD4 T cells found in the blood 7 d after immunization (r = 0.85; P = 0.03) (Fig.…”

Section: Plasma Cxcl13 Is Correlated With Gc Activity In Macaques Aftermentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

278

291

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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“…To further explore functional impairment in pTfh cells in HIV progressors compared to controllers, we next performed coculture assays to directly determine whether CD4 helper quality varies between PBMCs derived from these two cohorts in response to both global and antigen-specific stimulation, as previously shown (21,22). Specimens from both HIV VC and HIV EC were grouped for this analysis to achieve sufficient statistical power.…”

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection Butmentioning

confidence: 99%

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ϩ CD4 ϩ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ϩ CD4 ϩ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ϩ CD4 ϩ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ϩ CD4 ϩ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ϩ CD4 ϩ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

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Induction of ICOS ⁺ CXCR3 ⁺ CXCR5 ⁺ T _H Cells Correlates with Antibody Responses to Influenza Vaccination

Cited by 539 publications

References 45 publications

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

CXCL13 is a plasma biomarker of germinal center activity

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

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Induction of ICOS + CXCR3 + CXCR5 + T H Cells Correlates with Antibody Responses to Influenza Vaccination

Cited by 539 publications

References 45 publications

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

CXCL13 is a plasma biomarker of germinal center activity

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

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Product

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Induction of ICOS ⁺ CXCR3 ⁺ CXCR5 ⁺ T _H Cells Correlates with Antibody Responses to Influenza Vaccination