Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms

Ho, Jason; Moir, Susan; Malaspina, Angela; Howell, Melissa L.; Wang, Wei; DiPoto, Angela C.; O’Shea, Marie A.; Roby, Gregg; Kwan, Richard; Mican, JoAnn M.; Chun, Tae‐Wook; Fauci, Anthony S.

doi:10.1073/pnas.0609515103

Cited by 74 publications

(77 citation statements)

References 45 publications

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“…Also in HIV-1 infection, infiltration of B cell follicles with effector CD8 T cells has been observed, and they may be involved in destruction of LN architecture, as occurs in HIV-1-infected patients during progression to AIDS (15). Moreover, B cells in HIV-1-infected patients have a high turnover; this has been attributed at least in part to increased susceptibility to Fas-mediated cell death (65,66). This is compatible with events in CD70-T cell Tg mice, indicating that CD70-driven influx of effector T cells may contribute to disruption of B cell responses in chronic infection.…”

Section: Discussionmentioning

confidence: 99%

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Beishuizen

Kragten

Boon³

et al. 2009

The Journal of Immunology

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CD70 provides costimulation that enhances effector T cell differentiation upon binding of its receptor, CD27. During chronic immune activation, CD70 is constitutively expressed on activated immune cells, and this induces T cell-driven disruption of neutralizing Ab responses via an unknown mechanism. We used CD70-transgenic mice to investigate the effect of constitutive expression of CD70 on T cell-dependent B cell responses. CD70 induced up-regulation of the B cell follicle homing chemokine receptor CXCR5 on T cells, enabling not only CD4 but also CD8 T cells to infiltrate the B cell follicles. CD70-transgenic mice failed to develop productive germinal center formation and displayed impaired IgG Ab responses. Defective germinal center B cell differentiation was critically dependent on CD70-mediated CD27 signaling in T cells, and involved Fas-dependent impairment of germinal center B cell differentiation. Thus, CD70-driven costimulation enables T cells to terminate B cell responses, thereby compromising durable Ab production. Our findings imply that the CD70- and CD27-driven costimulatory axis may be involved in shutdown of B cell responses before clearance of Ag. Because CD70 is expressed constitutively in chronic viral infections such as HIV-1 infection, this mechanism may also contribute to defects in humoral immunity associated with this disease.

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Section: Discussionmentioning

confidence: 99%

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Beishuizen

Kragten

Boon³

et al. 2009

The Journal of Immunology

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“…These activated B cells have previously been shown to be highly susceptible to cell death by CD95-mediated extrinsic apoptosis. 42 Furthermore, plasmablasts, a subpopulation of short-lived Ki-67 ϩ B cells likely to be responsible for increased B-cell turnover in HIV-viremic individuals, 4,9,42 were more abundant in early HIV-infected individuals before ART and normalized after ART. Finally, immature/transitional B cells, which have been shown to be highly susceptible to cell death by intrinsic apoptosis, 42 were more abundant in chronically HIV-infected individuals before initiation of ART and significantly depleted after ART.…”

Section: Discussionmentioning

confidence: 99%

“…42 Furthermore, plasmablasts, a subpopulation of short-lived Ki-67 ϩ B cells likely to be responsible for increased B-cell turnover in HIV-viremic individuals, 4,9,42 were more abundant in early HIV-infected individuals before ART and normalized after ART. Finally, immature/transitional B cells, which have been shown to be highly susceptible to cell death by intrinsic apoptosis, 42 were more abundant in chronically HIV-infected individuals before initiation of ART and significantly depleted after ART. Collectively, the replacement of these various short-lived B cells before initiation of ART with longer-lived naive and resting memory B cells after ART in HIV-infected individuals treated during the early and chronic stages of infection may help explain the increases in B-cell numbers observed in both groups, although redistribution from tissues cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Moir

Buckner

et al. 2010

Blood

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238

263

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IntroductionNumerous perturbations of B-cell phenotype and function have been described in HIV-infected individuals (reviewed in Cagigi et al 1 and Moir and Fauci 2 ). Phenotypic perturbations of B cells circulating in the peripheral blood include over-representation of activated, exhausted, and terminally differentiated B cells associated with HIV viremia 3-5 ; over-representation of immature/ transitional B cells associated with HIV-induced CD4 ϩ T-cell lymphopenia 6,7 ; and reduced representation of CD27 ϩ memory B cells associated with most stages of HIV infection. [8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens. 11,17,18 The latter is likely a reflection of both CD4 ϩ T-cell dependent and independent defects in B cells that arise in HIV-infected individuals, and especially in individuals with ongoing viral replication. Many of the functional B-cell defects described in HIV-viremic individuals can be improved with ART, although there is 1 important exception that has received relatively little attention. While B-cell responses against non-HIV antigens are either stabilized or increased after initiation of ART, 19-22 the reverse is often observed for B-cell responses against HIV antigens,15,23,24 suggesting that the humoral response against HIV is dependent on continuous HIV replication. In the most comprehensive study on B-cell responses after ART, Morris and colleagues described a rapid loss of HIV-specific B cells (actively secreting plasmablasts) during therapy, followed by a more gradual decrease in antibody titers against HIV in chronically infected individuals; the loss was even more rapid in early-treated individuals. 15 In a previous study of chronically HIV-infected individuals, we reported a reduction in B-cell numbers and the presence of perturbed B-cell subpopulations before initiation of ART followed by partial normalization 1 year after successful reduction in viremia by ART. 25 In a more recent study, 5 we identified a subpopulation of CD27 Ϫ tissue-like memory B cells within an abnormal CD21 lo B-cell compartment of the peripheral blood of chronically HIVviremic individuals; this subpopulation had been included within the activated B-cell compartment that we had previously described. 25 These CD27 Ϫ tissue-like memory B cells bore many features of exhausted cells, arising in the context of chronic immune activation, and with features that include expression of multiple inhibitory...

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“…40 Malaspina et al 6,25 have described an immature/transitional B-cell phenotype in both HIV-infected individuals as well as in patients with idiopathic CD4 ϩ T lymphopenia. These cells are prone to intrinsic apoptosis due to reduced expression of Bcl-2 and Bcl-xL, 41 and their frequency is correlated directly with serum levels of IL-7. 25 In the present study, a single injection of rhIL-7 led to the emergence of this phenotype, showing clearly that IL-7 can affect maturation of circulating human B cells.…”

Section: Discussionmentioning

confidence: 99%

IL-7 administration drives T cell–cycle entry and expansion in HIV-1 infection

Sereti

Dunham

Spritzler

et al. 2009

Blood

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293

273

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Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebocontrolled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 g/kg and a maximum tolerated dose of 30 g/kg.

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Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms

Abstract: Perturbations of B cells in HIV-

Cited by 74 publications

References 45 publications

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

IL-7 administration drives T cell–cycle entry and expansion in HIV-1 infection

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