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Front. Immunol. | doi: 10.3389/fimmu.2019.00630

PD-1 primarily targets TCR signal in the inhibition of functional T cell activation

  • 1Institute of Advanced Medical Sciences, Tokushima University, Japan

Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced TFH cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.

Keywords: T cell receptor (TCR), co-receptor, PD-1, CD28, ICOS, Follicular helper T, Cytokine producing capability

Received: 08 Jan 2019; Accepted: 08 Mar 2019.

Edited by:

Shohei Hori, The University of Tokyo, Japan

Reviewed by:

Hisashi Arase, Osaka University, Japan
Eric Huseby, University of Massachusetts Boston, United States  

Copyright: © 2019 Mizuno, Sugiura, Shimizu, Maruhashi, Watada, Okazaki and Okazaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Taku Okazaki, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan,