Manipulating the PD-1 pathway to improve immunity

Abstract

PD-1 is an inhibitory receptor induced in T cells by antigen stimulation and sustained PD-1 expression plays a key role in T cell dysfunction. Blocking PD-1 signaling rescues exhausted T cells and is an effective treatment for chronic infections and cancer. Nonetheless, combining PD-1 pathway blockade to therapeutic vaccination should further improve T cell rescue. PD-1 is induced shortly after T cell priming, but little is known about the role of PD-1 in the initiation of immune responses. In addition, the PD-1 pathway may also modulate humoral responses, since both B cells and Tfh cells express PD-1. Therefore, even though much progress has been achieved by manipulation of the PD-1 pathway to rescue exhausted T cells, this powerful immunotherapy could still be further exploited.

Figure 1. PD-1 inhibits TCR/CD28 signaling

Upon engagement with PD-L1 or PD-L2, PD-1 is phosphorylated at both thyrosine containing motifs ITIM and ITSM. The phosphatase SHP2 (and possible SHP1 as well) is recruited to phosphorylated ITSM. SHP2 dephosphorylates phosphatidylinositol-3-kinase (PI3K) and ZAP70/CD3ζ, ultimately attenuating TCR/CD28 signaling and T cell activation [–11].

Figure 2. Potential role of the PD-1 pathway in B cell responses

A. Naïve T cells interact with dendritic cells (DCs) presenting cognate antigen and initiate commitment to different CD4 T helper (Th) lineages. Upon activation all CD4 cells express PD-1, but PD-1 expression is maintained and further increase in CD4 T cells that interact with cognate B cells and fully commit to Tfh lineage. Tfh cells express CXCR5 and migrate to the germinal center (GC) where they select high affinity B cells by providing IL-21 and CD40L. GC B cells that receive T cell help survive and differentiate into memory and plasma cells. Reports have shown that B cells express PD-1 upon activation, and PD-1 expression is maintained in GC and memory B cells. In addition, it has been reported that GC and memory B cells express PD-L2. PD-L1 expression is ubiquitous and was shown in the figure only in situations where engagement with PD-1 has been demonstrated to occur [,–43] B.PD -1 is expressed by CXCR5+ Tregs that limit GC reactions, and PD-1 engagement suppresses Tregs [43,48].

Figure 3. PD-1 pathway blockade promotes T cell activation and elimination of infected cells

During chronic infections, antigen specific T cells are exhausted due to PD-1 inhibitory signals and lack of positive co-stimulation. PD-1 pathway blockade promotes T cell activation by shifting the balance of signals delivered by cognate APCs from suppressive to activating. When rescued T cells recognize antigen in the periphery, in the absence of PD-1 engagement, T cells can assume full effector function and eliminate target cells [35]. Similar mechanisms also occur in cancer patients.