New therapy to revert dysfunctional antibody responses during HIV-1 infection (original) (raw)
All subsets of resting, activated, and tissue memory B cells in noninfected and SIV-infected animals analyzed by Titanji et al. expressed high levels of PD-1, with mBAct cells expressing the highest level of PD-1 and accounting for the largest number of PD-1+ cells (3). The depletion of mBAct cells shown to occur in rapid progressors related to high PD-1 expression. However, more studies are needed to clarify why signaling through PD-1 leads to depletion of mBAct cells only in rapid progressors, despite similar preinfection PD-1 expression levels on mBAct cells of rapid and typical progressors. The involvement of other apoptotic pathways, including Fas (3), and differential expression of the PD-1 ligands PD-L1 and PD-L2 in rapid and typical progressors may account for this difference.
PD-1 was first described as a negative regulatory molecule, the expression of which increases on T cells during activation (11). PD-1 expression during chronic viral infections has been linked to an exhausted phenotype, in which T cells are burned out and do not exert their effector functions. PD-L1 and PD-L2 are broadly expressed on dendritic cells, macrophages, B cells, and T cells. A role for PD-1 in negative regulation of B cell responses has been suggested by the findings that PD-1 inhibits BCR signaling through recruitment of src homology 2 domain–containing tyrosine phosphatase 2 (SHP-2) to its phosphotyrosine (12) and that PD-1–deficient mice develop antibody-mediated autoimmune diseases (13). A new view has recently emerged on the contribution of PD-1 signaling to the regulation of humoral immunity: interaction of PD-1 ligands on B cells with PD-1 on T cells was shown to exert a positive effect on antibody production by affecting the quality of germinal center (GC) responses and by fine-tuning the regulation of long-lived plasma cell formation (14). In the absence of PD-1 signals, augmented B cell death in GCs was reported to occur, with lower numbers of long-lived plasma cells formed (14).
Limited information is currently available on the autocrine role of PD-1 and PD-1 ligands in B cell responses and on the function of PD-1 on B cells in GC formation (15). Titanji and colleagues postulate a role for PD-1 signaling in regulating the survival/apoptosis of mBAct cells during SIV infection (Figure 2A), since in vitro exposure of B cells from SIV-infected macaques to PD-L1 expressed on a cell line increased mBAct cell apoptosis (3). Noticeably, upon these conditions, mBAct cells from control, noninfected animals did not die, even though they expressed similar levels of PD-1, which suggests that expression of proapoptotic factors prevails over that of antiapoptotic factors in mBAct cells of infected animals, especially fast progressors, and that differential expression of PD-L1 and PD-L2 may distinguish infected from noninfected animals. The cellular source of PD-L1 and PD-L2 in the SIV-infected macaques was not investigated. A previous study indicated that PD-L1 upregulation occurs in several cell types, including B cells, in progressive HIV-1 infection (16); however, more studies in SIV-infected animals are needed to define to what extent B cells express PD-L1 and/or PD-L2 and whether these ligands induce apoptosis of mBAct cells.
Biological action of PD-1 blockade on mBAct cells and antibody production during SIV infection. (A) As shown by Titanji and colleagues, PD-1 on mBAct of rapid progressors leads to apoptosis of these cells (3). The signal to undergo PD-1–mediated apoptosis can be provided in an autocrine fashion from PD-1 ligands present on B cells, or from PD-1 ligands on Th cells. In this context, it is likely that PD-1 present on Th cells does not receive signaling from PD-1 ligands present on B cells, since they are engaged in autocrine binding to PD-1 on B cells. (B) One possible interpretation of the data presented by Titanji et al. (3) is that upon PD-1 blockade, the autocrine binding of PD-1 to PD-1 ligands is inhibited, thus preventing apoptosis of B cells. Thus, blocking PD-1 on B cells can improve the possibility for these cells to produce specific antibodies to SIV and other microbial antigens, by channeling T cell help toward B cells in GCs.