B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling

Sadiye Amcaoglu Rieder,Natalie White,Jodi L Karnell,Catherine Menard,Roland Kolbeck,Jingya Wang,Geoffrey Stephens,Christopher E Rudd,Ariful Qadri

doi:10.1038/s41423-020-0361-7

Sadiye Amcaoglu Rieder, Natalie White + Show 7 more

Open Access

https://doi.org/10.1038/s41423-020-0361-7

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Abstract

Modulation of T-cell responses has played a key role in treating cancers and autoimmune diseases. Therefore, understanding how different receptors on T cells impact functional outcomes is crucial. The influence of B7-H7 (HHLA2) and CD28H (TMIGD2) on T-cell activation remains controversial. Here we examined global transcriptomic changes in human T cells induced by B7-H7. Stimulation through TCR with OKT3 and B7-H7 resulted in modest fold changes in the expression of select genes; however, these fold changes were significantly lower than those induced by OKT3 and B7-1 stimulation. The transcriptional changes induced by OKT3 and B7-H7 were insufficient to provide functional stimulation as measured by evaluating T-cell proliferation and cytokine production. Interestingly, B7-H7 was coinhibitory when simultaneously combined with TCR and CD28 stimulation. This inhibitory activity was comparable to that observed with PD-L1. Finally, in physiological assays using T cells and APCs, blockade of B7-H7 enhanced T-cell activation and proliferation, demonstrating that this ligand acts as a break signal. Our work defines that the transcriptomic changes induced by B7-H7 are insufficient to support full costimulation with TCR signaling and, instead, B7-H7 inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling.

Highlights

Modulation of T-cell responses with biologics has been one of the greatest advances in medicine in the last decade.[1,2,3] We have a better understanding of T-cell biology and are able to fine-tune T-cell responses with different treatment options in cancer and autoimmunity.[4,5] Some examples of treatment modalities include checkpoint inhibitors such as α-PD-L1 antibodies in cancer and a CTLA-4 Ig protein for the treatment of autoimmune conditions.[6,7] In cancer and autoimmunity, T-cell activation is dysregulated in opposite ways
We sequenced OKT3 and control Fc (Ctrl Fc)-treated T cells, and this treatment did not significantly change gene expression when compared with OKT3 stimulation alone, as the samples clustered very closely on the Principal Component Analysis (PCA) plot (Supplementary Fig. 1b)
808 genes were upregulated and 76 genes were downregulated with OKT3 and B7-1 treatment, whereas 424 genes were upregulated and 38 genes were downregulated with OKT3 and B7-H7 treatment when compared with OKT3 stimulation alone (Fig. 1b)

Summary

Introduction

Modulation of T-cell responses with biologics has been one of the greatest advances in medicine in the last decade.[1,2,3] We have a better understanding of T-cell biology and are able to fine-tune T-cell responses with different treatment options in cancer and autoimmunity.[4,5] Some examples of treatment modalities include checkpoint inhibitors such as α-PD-L1 antibodies in cancer and a CTLA-4 Ig protein for the treatment of autoimmune conditions.[6,7] In cancer and autoimmunity, T-cell activation is dysregulated in opposite ways. There is a lack of T-cell infiltration and activation, whereas in autoimmunity T-cell activity is augmented. The process of T-cell activation is intricate, involves many different players, and is tightly controlled.[8] Proper activation of T cells requires two important signals: signal 1 (the binding of T-cell receptor--TCR to peptide antigen-bound major histocompatibility complex, MHC) and signal 2

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