T Cell Activation and Immune Checkpoint Regulation

T cells lie at the heart of adaptive immunity, recognising peptide antigens via the T cell receptor (TCR) and undergoing activation only when signals from co-stimulatory receptors complement antigen engagement. Upon antigen recognition, co-stimulatory molecules such as CD28 amplify kinase cascades and transcriptional programmes that drive proliferation, cytokine production and effector differentiation. To avert tissue damage and autoimmunity, a parallel set of inhibitory receptors—collectively termed immune checkpoints—dampens T cell responses once a threat is contained. Chief among these are cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), which recruit phosphatases to oppose TCR-driven phosphorylation events. More recently, the B and T lymphocyte attenuator (BTLA) and its ligand, herpesvirus entry mediator (HVEM), have emerged as critical modulators of T cell stimulation and tolerance. Dysregulation of checkpoint pathways underpins chronic infections, autoimmunity and cancer escape. Blockade of inhibitory receptors has revolutionised oncology, yet limited response rates and immune-related adverse events underscore the need to deepen mechanistic insight, identify novel targets and refine combination strategies. Advances in structural biology, murine models and human cell platforms are illuminating the molecular choreography of co-stimulatory and co-inhibitory signals, thereby guiding the design of next-generation immunotherapies with improved efficacy and safety profiles.

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T Cell Activation and Immune Checkpoint Regulation publication trend

The graph below shows the total number of articles in t cell activation and immune checkpoint regulation across all publications each year (not limited to Nature Index journals).

Technical terms

T cell receptor (TCR): A complex of proteins on T cells that recognises peptide–MHC complexes, initiating adaptive immune responses.

Immune checkpoint receptor: Surface molecules that deliver inhibitory signals to T cells, preventing excessive activation and maintaining self-tolerance.

CTLA-4: Cytotoxic T lymphocyte-associated antigen-4, an inhibitory receptor that competes with CD28 for ligand binding and recruits phosphatases to attenuate TCR signals.

PD-1: Programmed cell death-1, an inhibitory receptor that binds PD-L1/PD-L2 and dampens T cell proliferation and effector function.

BTLA: B and T lymphocyte attenuator, an inhibitory receptor in the CD28 family that engages HVEM to suppress lymphocyte activation.

HVEM: Herpesvirus entry mediator, a member of the TNF receptor superfamily that interacts with BTLA and other ligands to modulate immune responses.

References

1. Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy. Molecular Cancer (2023).
2. BTLA biology in cancer: from bench discoveries to clinical potentials. Biomarker Research (2024).
3. Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors. Journal for ImmunoTherapy of Cancer (2023).