PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Blockade antibodies targeting the immunoinhibitory receptor Programmed Cell Death protein 1 (PD-1) enhance anti-tumor T cell activity.
• Clinical benefits of PD-1 blockade are restricted to a subset of patients.
• The B and T lymphocyte attenuator (BTLA) receptor, structurally similar to PD-1, is implicated in resistance to PD-1 targeted therapy, but its precise mechanism and differences from PD-1 remain debated.

Purpose of the Study:

• To compare the mechanisms by which BTLA and PD-1 regulate T cell signaling and recruit effector molecules.
• To investigate the roles of SHP1 and SHP2 phosphatases in BTLA and PD-1 mediated T cell suppression.
• To determine if BTLA and PD-1 can inhibit T cell function independently of SHP1 and SHP2.

Main Methods:

• Comparative analysis of effector molecule recruitment by BTLA and PD-1.
• Assessment of T cell signaling regulation by BTLA and PD-1.
• Functional assays using primary T cells deficient in SHP1 and SHP2 phosphatases.

Main Results:

• PD-1 selectively recruited SHP2, while BTLA preferentially recruited SHP1, suggesting distinct phosphatase engagement.
• Both PD-1 and BTLA potently inhibited T cell proliferation and cytokine production, even in the absence of SHP1 and SHP2.
• In SHP1/SHP2 double-deficient T cells, PD-1 and BTLA-mediated inhibition was more transient compared to wild-type T cells.

Conclusions:

• BTLA and PD-1 employ distinct mechanisms for recruiting phosphatases (SHP1 vs. SHP2).
• Both PD-1 and BTLA possess the capacity to suppress T cell signaling through pathways independent of SHP1 and SHP2.
• These findings offer new insights into the differential regulation of T cell immunity by PD-1 and BTLA, potentially impacting cancer immunotherapy strategies.