Simian immunodeficiency virus infection in rhesus macaques induces selective tissue specific B cell defects in double positive CD21+CD27+ memory B cells

doi:10.1016/j.clim.2011.04.018

Clinical Immunology

Volume 140, Issue 3, September 2011, Pages 223-228

https://doi.org/10.1016/j.clim.2011.04.018 Get rights and content

Abstract

B cell dysfunction represents a central feature in HIV infection and pathogenesis. Our recent studies have shown that peripheral and lymphoid double positive CD21+CD27+ B cells were able to become activated and proliferate at higher rates than other B cell subpopulations. Increased proliferation of tonsillar memory B cells was identified compared to other tissues examined. Here, we demonstrate the decreased proliferation of tonsillar memory (CD21+CD27+) B cells during acute SIV infection also suggests that these cells may play an important role in SIV pathogenesis. Our findings demonstrate that SIV infection may induce selective defective responses in specific tissues, by suppressing memory B cell proliferation in tissues.

Highlights

► DP CD21+CD27+ B cells were able to become activated and proliferate at higher rates. ► Increased proliferation of tonsillar memory B cells were identified. ► Decreased proliferation of tonsillar memory B cells during acute SIV infection.

Introduction

Virus-induced immune-cell activation is one of the few widely accepted hallmarks of HIV/SIV pathogenesis and disease progression. HIV/SIV infection has been associated with a wide range of B cell defects, including increased frequencies of activated and terminally differentiated B cells expressing low levels of CD21 [1], [2], polyclonal hypergammaglobulinemia and the presence of immature/transitional CD10+ or exhausted CD27 negative B cells in blood [3], [4], [5], [6], [7], exhaustion of tissue-like memory (CD20(hi)/CD27(−)/CD21(lo)) B cells [8] and loss of memory B cell populations [9]. Early loss of B cells in spleen, lymph nodes and peripheral blood (PB) [10], [11], [12], [13] in SIV and disruption of gut germinal center during acute HIV infection [14] may be an indicator of the early failure of adaptive immune responses. Although studies have been performed to understand the role of B cells in SIV pathogenesis by artificially depleting B cells [15], [16], the dynamics and mechanism of B cell loss during acute phase of SIV infection are not well characterized. Our recent studies have shown that double positive (DP) CD21+CD27+ B cells are memory cells that are capable of antibody production by polyclonal activation, and without additional help from T cells [17]. Memory CD21+CD27+ B cells were predominant in all lymphoid tissues except for PB. DP CD21+CD27+ B cells were also able to activate and proliferate at higher rates than other B cell subpopulations [17]. In this study, we examined and compared levels of proliferation of T cells and different B cell subsets in lymphoid tissues to correlate their rates of proliferation with plasma viral load in SIV infected rhesus macaques (RMs).

This study shows that tonsillar CD21+CD27+ B cells are highly proliferating B cells compared to other tissues examined. Furthermore, these data demonstrate differences in proliferative responses of nonhuman primate B memory (CD21+CD27+) cell subsets and suggest that SIV infection may induce early defective responses in specific B cell subsets in specific tissues.

Section snippets

Animals, virus, BrdU, and tissue sampling

Twenty female and 2 male Indian RMs (Macaca mulatta) between 3 and 16 years of age, which were initially negative for HIV-2, SIV, type D retrovirus and STLV-1 infection were examined in this study (Table 1). All macaques were given the nucleotide analog BrdU (60 mg/kg in sterile saline, Sigma) intraperitoneally 24 h prior to euthanasia and tissue collection [17]. Ten female and 2 male RMs were infected either through intravenous, intravaginal or intrarectal route with 10–1000 TCID₅₀ SIV_MAC251.

Results and discussion

Since we previously showed more DP CD21+CD27+ B cells had the capacity to produce antibodies following polyclonal stimulation (and without T cell help), and higher rates of proliferation than their SP counterparts [17], here we compared differences in proliferation rates in both T and B cell subsets from normal and SIV_MAC251 infected RMs. Ten normal and 12 SIV_MAC251 infected RMs (Table 1) were inoculated with BrdU 24 h prior to sampling to detect cells in S-phase (DNA synthesis) of division. Of

Conflict of interest

The authors declare no financial or commercial conflict of interest.

Acknowledgments

We thank Maryjane Dodd, Janell LeBlanc, Linda Green, Maury Duplantis, Nancy Parr, Lara Doyle, and all animal care staff of the department of veterinary medicine for their technical assistance. We also thank Drs. Preston Marx, Gus Kousoulas and Vida Dennis for their support in this study. The work was supported by NIH grants P20 RR020159, R21 AI080395 (BP) and RR000164, R01 AI084793 (RSV), and amfAR grant-106719-40-RGRL (BP).

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However, in macaque PBMC a fairly large proportion of B-cells is double negative for CD21/CD27 [9,10]. The macaque mucosal memory B-cell profile presented here (Fig. 1) confirms a previous report of similarly double negative mucosal memory B-cells [10] essentially lacking CD27 in contrast to other reports [11,12]. We know that previous infection with SHIVSF162P4 does not affect CD27 expression, as data from 60 healthy rhesus macaques show the same staining pattern in the rectal mucosa (our unpublished data).
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Brief communicationSimian immunodeficiency virus infection in rhesus macaques induces selective tissue specific B cell defects in double positive CD21+CD27+ memory B cells

Abstract

Highlights

Introduction

Section snippets

Animals, virus, BrdU, and tissue sampling

Results and discussion

Conflict of interest

Acknowledgments

Blood

J. Allergy Clin. Immunol.

Virology

Blood

Vaccine

Clin. Immunol. Immunopathol.

Virology

Blood

Virology

Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily

J. Exp. Med.

HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals

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

Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7

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

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

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

Brief communication
Simian immunodeficiency virus infection in rhesus macaques induces selective tissue specific B cell defects in double positive CD21+CD27+ memory B cells