Last week, a research team led by Susan Moir from Anthony Fauci’s lab at NIAID published a potentially important paper on B cell dysfunction in HIV infection. It’s something of a sad commentary on the quality of science reporting in the mainstream media that, despite the issuance of a press release by NIAID, the study seems to have received no coverage whatsoever. Admittedly, immunology research can appear impenetrably arcane to the uninitiated, but it’s a shame that good science frequently goes uncovered while – as we’ve seen recently with stories on vaccine trials - misinformation about HIV research can get plastered across front pages.
Historically, research into the effects of HIV infection on B cell populations has been limited compared to the more extensive investigations into the impact of the virus on T cells. But over the past several years, Susan Moir and colleagues have conducted an impressive array of studies that have opened a window onto this obscure area of HIV pathogenesis. Many of the insights gained from these and other studies are described by Moir and Fauci in a free review in the special issue of the Journal of Allergy & Clinical Immunology mentioned in a prior post. What is fairly striking – although perhaps not entirely surprising - is that HIV infection appears to impact B cell populations in ways that are broadly similar to the effects of the virus on T cell populations. In both cases, HIV-induced immune activation appears to be driving the changes, which involve declines in the numbers of resting naïve and memory B cells and increases in the number of activated and dysfunctional B cells.
In this study, detailed evaluation of B cell phenotypes in people with HIV identified a subset of B cells that expressed high levels of inhibitory receptors (reminiscent of data on CTLA-4 and PD-1 expression on T cells in people with HIV) and displayed poor proliferative capacity. Analysis of the replicative history of these B cells suggests that they became dysfunctional and exhausted while en route differentiating from naïve to classical memory B cells. Interestingly, the population was enriched for HIV-specific responses, again echoing data showing that dysfunctional HIV-specific T cell responses accumulate over the course of disease (see for example this figure from a comprehensive analysis of HIV-specific CD4 and CD8 T cell responses in people at varying stages of disease progression; participant #21 - in whom around 18% of CD8 T cells and 3% of CD4 T cells make interferon gamma in response to HIV antigens - has a CD4 count of 181 and is the only participant with an AIDS diagnosis. The total number of HIV-specific T cells in this individual is actually certainly far greater because the capacity for interferon gamma production is lost by fully exhausted T cells and the consensus peptides used in the study do not capture the HIV sequence variation that occurs in an individual over time).
The theme that seems to be emerging from these data is that HIV, by preferentially infecting HIV-specific CD4 T cells, compromises the CD4 response from the very earliest stages of infection, and the lack of a fully functional HIV-specific memory CD4 T cell response deprives both HIV-specific B cells and HIV-specific CD8 T cells of the help they require to properly differentiate into memory cells. It would be interesting to know if the accumulation of dysfunctional HIV-specific T cell and B cell responses is linked to the loss of memory responses to opportunistic pathogens in people with AIDS.
In a related development, a new paper in the Journal of Immunology suggests that, despite their differences, the development of memory B cells and T cells is associated with gene transcription programs that have distinct similarities (abstract and link below).
The Journal of Experimental Medicine
Published online July 14, 2008
doi:10.1084/jem.20072683
BRIEF DEFINITIVE REPORT
Susan Moir1, Jason Ho1, Angela Malaspina1, Wei Wang1, Angela C. DiPoto1, Marie A. O'Shea1, Gregg Roby1, Shyam Kottilil1, James Arthos1, Michael A. Proschan2, Tae-Wook Chun1, and Anthony S. Fauci1
1 Laboratory of Immunoregulation and 2 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892
Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27–/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27–/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.
The Journal of Immunology, 2008, 181: 1859-1868.
W. Nicholas Haining, Benjamin L. Ebert, Aravind Subrmanian, E. John Wherry, Quentin Eichbaum, John W. Evans, Raymond Mak, Stephen Rivoli, Jennifer Pretz, Jill Angelosanto, John S. Smutko, Bruce D. Walker, Susan M. Kaech, Rafi Ahmed, Lee M. Nadler and Todd R. Golub
After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.
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