Microorganism-Derived Proteins

Introduction to Microorganism-Derived Proteins

Microorganism-derived proteins are a group of proteins that have been widely used in different clinical applications. In the past few years of studies, results have suggested that these microbial proteins, such as staphylococcal enterotoxins and toxin listeriolysin O (LLO), can be regarded as super-antigens (SAgs) for activating T cell and releasing pro-inflammatory cytokines. In general, these proteins can closely bind with the major histocompatibility complex (MHC) class II molecules expressed on antigen-presenting cells (APCs), and further bind to the variable region of T cell receptor (TCR) β-chain. Till now, more than 50 TCR Vβ domains have been confirmed that can bind to specific microbial proteins. Moreover, recent studies have demonstrated that these proteins are related to the abnormal release of a large number of cytokines which can lead to several serious adverse reactions, such as toxic shock. However, numerous data have indicated that most of the microbial proteins display higher affinities towards human MHC class II antigens and can be used for the development of T cell therapy.

Fig.1 The tumor cell recognition mechanism of γδ T cells. (Liu, 2020)

The Role of Microorganism-Derived Proteins in γδ T Cell Therapy

Currently, previous reports have revealed that two main types of T cells, αβ T cells, and γδ T cells, express different types of TCRs, αβ TCR and γδ TCR, respectively, are composed of specific TCR chains and CD3 subunits. In particular, γδ T cells have aroused much attention due to their ability to produce massive cytokines and the potential role in new T cell therapy discovery. For example, recent research has shown that IL-17-producing γδ T cells display anti-bacterial capacity and can promote osteoblast differentiation in certain disease conditions. Moreover, γδ T cells can determine their maturation and effector function by using different TCR/CD3 complexes and specific downstream signaling pathways. Besides, a wide variety of microorganism-derived proteins can be treated as γδ TCR-specific signaling proteins to identify the endogenous γδ TCR ligands that control γδ T cell functions. As a consequence, it is important to determine whether these microbial proteins can be used for improving the performance of γδ T cell therapy in various disease treatments.

Fig.2 Structure of TIGIT-PVR Complex. (Hong, 2018)

Types of Microorganism-Derived Proteins

• Staphylococcal Enterotoxins

Normally, staphylococcal enterotoxins (SEs) can promote the proliferation of γδ T cells and regulate the lysis of target cells. In the studies reported, the proliferative response of γδ T cells can be achieved in an MHC class II independent manner after stimulation with different SEs, such as SEA, SEB, SEC, and SEI. Moreover, the cytolytic activity of γδ T cells can be also regulated by SEA pulsed target cells or SE specific antibodies. As a result, there has been increasing interest in translating the unique potential of SEs into innovative γδ T cell immunotherapies.

• Toxin Listeriolysin O

γδ T cells are a unique type of T cell that is not restricted by conventional MHC antigens. The past few years have seen a wealth of data regarding the identification and validation of γδ T cell ligands. Toxin listeriolysin O (LLO), a type of cholesterol-dependent cytolysins, is produced by the pathogenic gram-positive Listeria monocytogenes. Up to now, LLO as a γδ T cell ligand has been confirmed and widely used for developing γδ T cell therapy against different human diseases, especially for malignant tumors.

• 6-kDa Early Secreted Antigenic Target Protein

6-kDa early secreted antigenic target protein (ESAT-6), a protein secreted by M. tuberculosis, has been used as a perfect vaccine candidate for treating Mycobacterium tuberculosis (Mtb) infection. The results have illustrated that the γδ T cell responses to ESAT-6 can be used to evaluate the active tuberculosis infection in patients. Meanwhile, it is also a potential target of γδ TCRs in the generation of novel T cell immunotherapy.

• Herpes Simplex Virus Glycoprotein I

Herpes simplex virus glycoprotein I (HSV-gI), a complex glycoprotein, can be recognized by expanded TCR-γδ cells in the absence of antigen-processing cells to trigger enough immune responses against HSV-1 infection. Nowadays, HSV-gI has become an antigenic ligand and may contribute to the generation of γδ T cell-mediated therapy.

• Tetanus Toxoid

Tetanus toxoid (TT), is an inactive tetanus vaccine that is used to prevent tetanus in humans. Recent studies have shown that TT can also induce a series of γδ T cell responses to Mycobacteria. Also, TT is capable of developing an immune-like cytokine phenotype, and therefore might be important targets for γδ TCR.

• Polyoma Virus Receptor

Polyoma Virus Receptor (PVR) is a ligand for DNAX accessory molecule-1 (DNAM-1). DNAM-1 can recognize the Vγ9Vδ2 T cells in tumor cells. Also, PVR is a key element of helping the Vγ9Vδ2 T cells target different tumor cells. As a result, PVR has become a new candidate target for developing new γδ T cell-based cancer immunotherapy in tumor therapy.

References

1. Liu, Y., et al. The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy. Cells. 2020, 9(5): 1206.
2. Hong, X., et al. Correlation of T cell immunoglobulin and ITIM domain (TIGIT) and programmed death 1 (PD-1) with clinicopathological characteristics of renal cell carcinoma may indicate potential targets for treatment. Medical science monitor: international medical journal of experimental and clinical research. 2018, 24: 6861.