Checking into the germinal centers: PD-1 regulates entry

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Science Immunology  05 Oct 2018:
Vol. 3, Issue 28, eaav4511
DOI: 10.1126/sciimmunol.aav4511


PD-1 functions on T follicular helper cells to dictate localization within lymph node germinal centers.

Program cell death protein 1 (PD-1) is an inhibitory B7 family member; it has been extensively studied for its role in inhibiting CD8+ T cell function within tumors or during chronic infections. This work has led to successful clinical use of checkpoint inhibitors to rejuvenate the antitumor T cell response. PD-1 is also a defining marker of CD4+ T follicular helper (TFH) cells, which are responsible for guiding B cell antibody production. What role it plays on TFH cell function is not well understood. Consistent with its inhibitory function, PD-1 does in fact constrain TFH cell development. However, recent work from Shi et al. demonstrates that PD-1 is also required to fine-tune the TFH-B cell humoral response by regulating TFH cell positioning within lymph nodes (LNs). As CD4+ T cells approach the follicle, they are rebuffed by bystander B cells expressing a ligand for PD-1, which dampens phosphoinositide-3 kinase (PI3K) signaling downstream of the chemokine receptor CXCR5 and thus slows T cell motility. As inducible T-cell costimulator (ICOS) enhances PI3K signals, theoretically only T cells with the highest level of ICOS can overcome this and make it through the inhibitory ring of B cells to the germinal center. PD-1 expression also blocks developing TFH cell distraction from chemokines expressed outside of the follicle by negatively regulating CXCR3 expression. All together then, PD-1 expression by recently activated CD4+ T cells helps to enforce a TFH cell concentration within the antigen-reactive B cell germinal center. An unresolved immunologic mystery is how naïve T cells—after early antigenic stimulation—“choose” a particular differentiation fate. In particular, T helper type 2 (TH2) and TFH cells require similar costimulatory signals from antigen presenting cells, express higher levels of CXCR5 than other T effector fates, and are concentrated in the same region of the LN during activation—the T-B border—where they are activated by type 2 conventional dendritic cells (cDC2s). Based on this recent work, differential expression of ICOS might be the tipping point toward TFH rather than TH2 differentiation. By overcoming PD-1 inhibition, strong ICOS signaling allows passage into the germinal center where the final stage of TFH differentiation occurs.

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