T Cell Co-Signaling Pathway: Ligand-Receptor Interactions

Overview of T Cell Co-signaling Ligand-Receptor Interactions

T cell activation requires two signals: 1) recognition of the antigenic peptide/major histocompatibility complex (MHC) by the T cell receptor (TCR) and 2) antigen-independent co-stimulation induced by interactions between co-signaling molecules expressed on antigen-presenting cells (APCs) and their T cell-expressed receptors. Engagement of the TCR in the absence of this second co-stimulatory signal typically results in T cell anergy or apoptosis. In addition, T cell activation can be negatively regulated by co-inhibitory molecules present on APCs. Therefore, integration of the signals transduced by co-stimulatory and co-inhibitory molecules following TCR engagement directs the outcome and magnitude of a T cell response including the enhancement or suppression of T cell proliferation, differentiation, and/or cytokine secretion. Most co-stimulatory and co-inhibitory molecules belong to either the Immunoglobulin (Ig) superfamily or Tumor Necrosis Factor (TNF) receptor superfamily and are further classified as members of the B7/CD28, butyrophilin, CD2/SLAM, TIM, or CD226 subfamilies of the Ig superfamily or as members of the type L or type V subfamilies of the TNF receptor superfamily. Many of these proteins are being investigated as potential targets for cancer immunotherapy as multiple studies have shown that the T cell co-stimulatory/co-inhibitory system can be exploited to improve anti-tumor immunity.

B7 proteins are a family of co-signaling molecules that primarily interact with T cell-expressed immune receptors belonging to the CD28 family (CD28, CTLA-4, PD-1, ICOS, and BTLA). Interactions between B7 and CD28 family members transduce both T cell co-stimulatory and co-inhibitory signals. Additionally, these interactions can have bidirectional effects (indicated by the two-headed arrows in the graphic). The B7 family consists of ten surface glycoproteins including B7-1/CD80, B7-2/CD86, B7-H1/PD-L1, B7-DC/PD-L2, B7-H2/ICOS L, B7-H3, B7-H4, B7-H5/VISTA, B7-H6, and B7-H7/HHLA2. Of these, B7-1/CD80 and B7-2/CD86 have been the most widely studied. Both B7-1/CD80 and B7-2/CD86 are expressed on APCs and can bind to T cell-expressed CD28 or CTLA-4. CD28 is constitutively expressed on naïve T cells and its interaction with B7-1/CD80 or B7-2/CD86 promotes T cell activation. In contrast, CTLA-4 expression is induced 24-48 hours following T cell activation. It binds to both B7-1/CD80 and B7-2/CD86 with higher affinity than CD28 and produces a co-inhibitory signal that down regulates the T cell response. B7-H1/PD-L1 and PD-L2/B7-DC also function as co-inhibitory molecules by signaling through the T cell-expressed PD-1 receptor. Significantly, blocking antibodies against CTLA-4, PD-1, or PD-L1 have been shown to improve the immune response in multiple different cancer models. Other B7 family proteins deliver co-stimulatory or co-inhibitory signals by binding to ICOS (B7-H2/ICOS L) or currently unidentified receptors (B7-H4, B7-H5/VISTA, B7-H7/HHLA2) as shown in the graphic. B7-H6 is an exception because unlike other B7 family proteins, it binds to the NKp30 activating receptor on natural killer cells (not shown). The BTLA protein is also distinct from other CD28 family receptors as it binds to the TNF receptor superfamily member, HVEM, to inhibit T cell activation.

Structurally, the butyrophilins are closely related to the B7 family proteins and appear to have similar immunomodulatory functions. To date, thirteen human butyrophilin proteins have been identified including BTN1A1, BTN2A1, BTN2A2, BTN2A3, BTN3A1, BTN3A2, BTN3A3, and the butyrophilin-like proteins, BTNL2, BTNL3, BTNL8, BTNL9, BTNL10, and SKINT-like (SKINTL). With the exception of BTNL2 and BTN3A2, butyrophilins are type I transmembrane proteins that contain one IgV-like and one IgC-like domain in their extracellular regions and a cytoplasmic B30.2 domain. The presence of this domain distinguishes the butyrophilins from the B7 family. Unlike other butyrophilins, BTNL2 has two extracellular IgV- and IgC-like domains and lacks the intracellular B30.2 domain, which is also absent in BTN3A2. Most butyrophilin proteins that have been characterized to date, including human BTN1A1, BTN2A2, BTN3A1, BTNL2, and mouse BTNL1, act through unidentified receptors to inhibit T cell proliferation and cytokine production. The exception is BTNL8 which enhances T cell proliferation and cytokine secretion. Further investigation is necessary to identify the butyrophilin receptors and determine the functions of the other butyrophilin family members.

Several members of the CD2/signaling lymphocyte activation molecule (SLAM) family of proteins have also been shown to regulate T cell co-signaling. The SLAM family currently consists of nine members, SLAM/CD150, CD48/SLAMF2, Ly9/SLAMF3, 2B4/SLAMF4, CD84/SLAMF5, NTB-A/SLAMF6/Ly108, CRACC/SLAMF7, BLAME, SLAMF8, and CD2F-10/SLAMF9. These proteins contain two or four extracellular Ig-like domains and most contain a cytoplasmic domain known as the immunoreceptor tyrosine-based switch motif (ITSM). SLAM family receptors are expressed on a variety of hematopoietic cell types including T cells, B cells, and dendritic cells and most are capable of homotypic interactions, allowing them to act as self-ligands. T cell activation is induced by homotypic interactions between APC- and T cell-expressed SLAM/CD150 and by binding of APC-expressed CD48/SLAMF2 (mice and rats) or CD58/LFA-3 (humans) to T cell-expressed CD2. Ly9/SLAMF3 and NTB-A/SLAMF6 also seem to function as T cell activating receptors. In contrast, CD48/SLAMF2 can inhibit T cell activation through an interaction with 2B4/SLAMF4. More research is needed to determine if other CD2/SLAM family proteins affect T cell co-signaling.

The T cell/transmembrane, immunoglobulin, and mucin (TIM) family and nectin- or nectin-like-binding receptors (CD226) are two additional subfamilies of IgSF molecules that regulate T cell activation. In humans, the TIM family consists of TIM-1, TIM-3, and TIM-4. TIM-4 is exclusively expressed on APCs and has both co-stimulatory and co-inhibitory effects on T cell activation. Binding of TIM-4 on APCs to TIM-1 on activated T cells promotes T cell proliferation and cytokine production. In contrast, TIM-4 has an inhibitory effect on naïve T cells, which do not express TIM-1, suggesting that TIM-4 can act through a currently unidentified receptor to prevent naïve T cell proliferation. The interaction between T cell-expressed TIM-3 and its ligand, Galectin-9, also inhibits T cell responses.

Nectin or nectin-like-binding receptors including DNAM-1/CD226, TIGIT, CRTAM, and CD96 are a new group of IgSF members that regulate the activities of CD8+ T cells and natural killer (NK) cells. DNAM-1/CD226 is expressed on several lymphoid and myeloid cell types and interacts with CD155/PVR or Nectin-2/CD112, which promotes the activation of CD8+ T cells and NK cells. TIGIT also binds Nectin-2/CD112 and CD155/PVR and can antagonize the effects of DNAM-1/CD226. TIGIT is primarily expressed on activated CD4+ and CD8+ T cells and ligation of TIGIT down regulates TCR-mediated activation and proliferation.

Several TNF receptor superfamily members have also been shown to affect T cell co-signaling. These proteins are characterized as type L or type V receptors based on their structures. A subset of members from the type L subfamily and all of the type V receptor subfamily have co-stimulatory activities. These include CD40/TNFRSF5, HVEM/TNFRSF14 (binding to Lymphotoxin alpha or LIGHT/TNFSF14), and DR3/TNFRSF25 from the type L subfamily, and 4-1BB/TNFRSF9, CD27/TNFRSF7, CD30/TNFRSF8, GITR/TNFRSF18, and OX40/TNFSF4 from the type V subfamily. HVEM/TNFRSF14 can also have co-inhibitory effects on T cell activation through its interactions with CD160 and BTLA.

To learn more, explore the following T cell co-signaling-related resources:

Current and Emerging Immune Checkpoint Targets for Immuno-Oncology Research eBook

Co-stimulatory and Co-inhibitory Molecules Research Area

B7-CD28 Family of Immune Checkpoint Proteins

Bioactive Proteins: Immune Checkpoint

Non-Human Primate Recombinant Proteins

Avi-tag Biotinylated Proteins

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