Role of PD-1 in regulating acute infections
Introduction
T cell responses are controlled by the balance of positive and negative regulatory pathways. Negative regulatory pathways are crucial for peripheral self-tolerance and preventing autoimmunity, and can function through signals delivered by cell surface inhibitory receptors, immunoregulatory cytokines, and regulatory T cells (Treg). These regulatory pathways also play an important role in the response to pathogens. Inhibitory receptors have received considerable attention recently for their role during chronic viral infections [1, 2, 3]. PD-1, an inhibitory receptor in the CD28 family, is highly expressed on dysfunctional CD8 and CD4 T cells during chronic infections including LCMV, HIV, HCV, and HBV and contributes to dampening antiviral T cell immunity [1, 2, 3].
The expression of inhibitory receptors by T cells is not unique to chronic infections, however, and T cell activation in many settings results in the upregulation of inhibitory molecules such as PD-1, CTLA-4, TIM-3, BTLA, LAG-3, CD244, and CD160 [4]. Early studies suggested that negative regulatory pathways are important to limit developing effector T cell responses and perhaps curb tissue damage [3, 5, 6]. Recent studies, however, suggest that the role of inhibitory receptors during acute infections is more complex. This review will focus on emerging data showing roles for PD-1 and its ligands in modulating effector and memory T cell responses during acute infections. To provide a context for these studies, we first will outline the stages of T cell differentiation and introduce the PD-1 pathway.
Section snippets
Effector and memory T cell differentiation following acute infections
The best understood developmental signals guiding T cell activation and differentiation are Signal 1 from antigen-TCR, Signal 2 from co-stimulation, and Signal 3 from inflammatory cytokines. The generation of effector and memory T cells can roughly be divided into four stages: 1) initial activation of naïve T cells by professional APC; 2) expansion, differentiation, and dispersal of effector T cells; 3) contraction of the effector response; and 4) establishment of a stable memory T cell
Introduction to PD-1
The Programmed Death (PD)-1 receptor has two ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is inducibly expressed on CD4 and CD8 T cells, NKT cells, B cells, monocytes, and some DC subsets upon activation [6, 21]. The PD-1 ligands differ in their expression [6, 21]. PD-L2 is inducibly expressed on DCs, macrophages, peritoneal B1 B cells, and bone marrow (BM)-derived mast cells. PD-L1 is expressed on B cells, DCs, macrophages, BM-derived mast cells, and T cells, and is further
Concluding remarks
The PD-1:PD-L pathway is best known for its ability to negatively regulate immune responses. Most of the evidence for this role, however, comes from models of tolerance, cancer or chronic infections. Recent studies are revealing clear roles for this pathway during acute infections. While many studies demonstrate a negative regulatory role for this pathway during acute infections, there are also some situations where an intact PD-1 pathway appears to enhance, rather than inhibit, immunity. The
Conflicts of interest
GJF, AHS and EJW have patents and receive patent royalties related to PD-1.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from the National Institutes of Health (NIH), BAA-05-11 and P01 AI078897 (to AHS, GJF and EJW), P01 AI56299 (to AHS and GJF), 1U19A1082630 (to GJF and EJW), AI08080192 and HL92565 (to GJF), and AI071309 (to EJW), and grants from the Dana Foundation and Ellison Medical Foundation (to EJW). Because of space restrictions, we were able to cite only a fraction of the relevant literature and apologize to colleagues whose contributions may not be appropriately
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