Background:  Several B cell subsets are over-represented in the peripheral blood of HIV-infected viremic individuals. Among these subsets are mature, activated B cells that likely arise from HIV-induced immune activation. The present study investigated a unique subset of memory B cells with immunoregulatory properties that has recently been described in the lymphoid tissue (tonsils) of normal individuals.

Methods:  Mature B cells were isolated from the peripheral blood of HIV-viremic individuals and fractionated into subsets by magnetic bead approaches. The replication history and immunoglobulin (Ig) diversity of each fraction were assessed by kappa-deletion recombination excision circle (KREC) and restriction enzyme-based hotspot assays, respectively. Proliferative properties and antigen-specific frequencies of each fraction were assessed by thymidine incorporation and enzyme-linked immunosorbent spot (ELISpot) assay, respectively, following ex vivo stimulation.

Results:  We observed in the peripheral blood of HIV-viremic individuals a memory B cell subset that has been recently described in tonsils of normal individuals and is defined by the expression of the inhibitory receptor, Fc-receptor-like-4 (FcRL4). FcRL4-expressing B cells were significantly more prevalent in the blood of HIV-viremic than in HIV-aviremic and HIV-negative individuals. FcRL4 was enriched on B cells with a tissue memory phenotype (CD27^-/CD21^lo), but not on B cells with a classic memory (CD27⁺) or naïve (CD27^-/CD21^hi) B cell phenotype. Tissue memory B cells expressed increased levels of tissue homing receptors CXCR3 and CD11c, and inhibitory receptors CD22, CD85j, LAIR-1, and CD72. Ig diversities and replication histories were lower in tissue compared to classic memory B cells. Proliferation in response to various B cell stimuli was lower for tissue memory B cells than for classic memory and naïve B cells. Remarkably, HIV-specific antibody-secreting cells (ASC) were enriched in tissue memory B cells, whereas total and influenza-specific antibody-secreting cells were enriched in classic memory B cells.

Conclusions:  HIV-specific B cell responses in the peripheral blood of HIV-infected individuals are enriched in a memory B cell subset formerly described in the lymphoid tissue (tonsils) of normal individuals, which is characterized by reduced replicative potential, reduced affinity maturation, and increased inhibitory properties. Premature senescence of B cells may help explain why antibody responses against HIV are largely ineffective.