The activation of T lymphocytes initiates their proliferation and yields a variety of effector functions that allow combating microbial infections, as well as developing tumors. The current paradigm is that full activation of T cells requires at least 2 signals upon contact with antigen-presenting cells (APCs) [1, 2].

Signal 1 is delivered through the interaction of the T cell receptor (TCR) and a specific antigenic peptide associated with an MHC (major histocompatibility complex) molecule on APCs. Signal 2 is delivered through the interaction of CD28, the prototypical T cell co-stimulatory molecule, and its ligands, CD80 or CD86, expressed by the APC. However, a number of other molecules, named immune checkpoints (IC), have been reported to regulate the onset and the limitations of T cell activities. PD-1 (programmed cell death 1) receptor and its ligand, PD-L1, are among the best characterized suppressive immune checkpoints [3].

Signal 1: TCR and [HLA::peptide]

The 'classical' and most represented TCR is an 80 to 90 kDa heterodimer composed of one α chain and one β chain. The αβTCR is a transmembrane protein expressed by developing and mature T cells. It features an extracellular ligand-binding pocket and a short cytoplasmic tail. Each αβTCR is restricted to a specific complex made of an antigenic peptide and a class I or class II MHC molecule. Human MHC molecules are also known as HLA (human leukocyte antigen). Because of its short cytoplasmic tail, the TCR, once engaged, lacks the ability to signal and requires non-covalent association with the CD3 to trigger downstream intracellular signaling and T cell activation [1, 2]. Importantly, signal 1 without co-stimulation results in T cell unresponsiveness or 'anergy', a tolerance mechanism that guards against premature activation.

Signal 2: CD28 and CD80/86

CD28 is a homodimeric and transmembrane protein expressed by T cells. Nearly all human CD4+ T cells and 50% of human CD8+ T cells express CD28. The CD28 interaction with CD80 (aka B7-1) or CD86 (aka B7-2) on APCs, in conjunction with TCR engagement, triggers a co-stimulation signal (signal 2). It results in T cell proliferation, cytokine production, cell survival, and cellular metabolism [1, 2].

IC signal: PD-1 and its ligands PD-L1 and PD-L2

— PD-1 (programmed cell death 1; also known as CD279) is a type I transmembrane protein expressed at the cell surface of activated and exhausted conventional T cells. PD-1 is an inhibitory immune checkpoint that prevents T-cell overstimulation and host damage. PD-1 interaction with its ligands PD-L1 and PD-L2 induces inhibition of TCR signaling [3].

— PD-L1 (programmed cell death ligand 1; also known as CD274 or B7-H1) is a transmembrane protein expressed at the cell surface of hematopoietic and nonhematopoietic cells and is induced by pro-inflammatory cytokines, such as in the tumor microenvironment [3]. PD-L1 is one ligand for PD-1, an inhibitory immune checkpoint receptor that is expressed by activated and exhausted T cells. PD-1:PD-L1 interaction induces inhibition of TCR signaling, thereby preventing T-cell overstimulation and host damage [3].

— PD-L2 (programmed cell death ligand 2; also known as CD273 or B7-DC) is a transmembrane protein that has more restricted expression in antigen-presenting cells, such as dendritic cells and macrophages [3, 4]. It serves as a second ligand for PD-1, complementing PD-L1 in mediating peripheral immune tolerance and maintaining immune homeostasis during infection [3-5]. Like PD-L1, PD-L2 is also co-opted by cancer cells and tumor-associated immune cells to suppress T cell-dependent anti-tumor immunity [5, 6].

Elevated PD-L2 expression has been observed in various malignancies, including lung, colorectal, and breast cancers, and is often associated with poor prognosis [7]. The continuous exploration of the clinical application of PD-L2 has brought exciting prospects for promoting cancer treatment, including small molecules, PD-L2-specific vaccines, and monoclonal antibodies (mAbs) [7]. However, the clinical approval of PD-L2-specific therapeutics for tumor treatment remains elusive, necessitating further investigation and discovery [7].

References:

1. Budd R.C. & Fortner K.A., 2017. Chapter 12 - T Lymphocytes. Kelley and Firestein's Textbook of Rheumatology (Tenth Edition). pages 189-206.
2. Smith-Garvin J.E. et al., 2009. T Cell Activation. Ann. Rev. Immunol. 27:591-619.
3. Ribas A. and Wolchock J.D., 2018. Cancer immunotherapy using checkpoint blockade. Science. 359:1350-55.
4. Latchman, Y. et al. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2, 261–268.
5. Yearley, J.H. et al. 2017. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 23, 3158–3167.
6. Rozali, E.N. et al. 2012. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol 2012, 656340.
7. Yang Y, et al. 2024. Programmed cell death-ligand 2: new insights in cancer. Front Immunol. 2024 Mar 28;15:1359532.

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