αβ T-cell receptor bias in disease and therapy (Review)

  • Authors:
    • Chun-Yan Wang
    • Pei-Fa Yu
    • Xiao-Bing He
    • Yong-Xiang Fang
    • Wen-Yu Cheng
    • Zhi-Zhong Jing
  • View Affiliations

  • Published online on: April 18, 2016     https://doi.org/10.3892/ijo.2016.3492
  • Pages: 2247-2256
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Abstract

The diversity and specificity of T cell receptors (TCR), the characteristics of T-cell surface marker, are central to the adaptive immunity. TCR variability is required for successful immunization coverage because this structural foundation is indispensable for the valid identification of short antigen peptides (derived from degraded antigens) that are presented by major histocompatibility molecules on the surfaces of antigen-presenting cells. Despite the vast T-cell repertoire, biased αβ TCR has become a common theme in immunology. To date, numerous examples of TCR bias have been observed in various diseases. Immunotherapy strategies that are based on αβ T cell responses are also emerged as a prominent component of clinical treatment. In the present review, we briefly summarize the current knowledge regarding basic structural information and the molecular mechanisms underlying TCR diversity. Moreover, we outline the role of TCR repertoire bias in some diseases, and its application for therapeutic interventions, as these play significant roles in disease progression, even with patients with a good prognosis.

1. Introduction

In mammals, thymus-derived T lymphocytes and bone-marrow-derived B lymphocytes can generate wide repertoires of antigen receptors [T-cell receptors (TCR) and B-cell receptors (BCR), respectively]. These receptors enable the recognition of a myriad of antigens in mammals through primary participation in cell-mediated immunity (T cells) and humoral immunity (B cells). T cells are divided into the following two subsets: αβ and γδ T cells, according to the heterodimeric, disulphide bond-linked TCR structure (1). The domain structures of TCRs are strikingly similar to the structure of immunoglobulin Fab fragments, therefore, TCRs are also classified as members of the immunoglobulin superfamily. However, unlike immunoglobulins, which recognize intact protein antigens, the complementarity-determining region (CDR) loops of TCRs only recognize processed fragments of antigens that are presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs), such as B cells, dendritic cells and macrophages (2,3). These antigens that are recognized by TCR family members include peptides, glycoproteins, lipids and small molecule metabolites. Thus, the resulting TCR-peptide-MHC complex is of great importance in cellular immunity.

αβ TCR are mainly expressed on the surfaces of αβ T and NKT cells, where they play a significant role in adaptive immune response by interacting with foreign antigens that are presented by MHC class I/II molecules on APCs. However, recent studies have described unconventional subsets of αβ T cells bearing TCRs that can recognize ligand antigens that are presented by molecules of the MHC-like CD1 family or vitamin B based metabolites that are bound to MHC-related protein 1 (MR1). These subsets include: i) mucosal-associated invariant T cells which exhibited restricted diversity and are involved in antibacterial immunity (4,5); and ii) invariant natural killer T (NKT) cells and germ-line-encoded mycolyl-reactive (GEM) T cells, which recognize glycolipids with respect to CD1d and CD1b, respectively (6,7). Other less well-characterized molecules are also known to recognize lipids that are presented by CD1a and CD1c molecules. In contrast, γδ TCRs are mainly expressed on the surfaces of γδ T cells, which comprise minority of the T cell pool but may represent more than half of the total T cells in tissues such as the gut and skin. In contrast to αβ TCRs, γδ TCRs recognize lipid-based antigens that are presented by CD1 molecules.

Regarding the functions of these two T-cell subsets, αβ T cells play an important role in protective immunity against various antigens, whereas γδ T cells were previously considered to be a necessary component of innate immunity, the term ‘T cell’ generally refers to αβ T cells. However, in recent years, they have been considered to share important characteristics of both the innate and adaptive immune responses and have garnered increasing attention in the field of immunotherapy because of their prominent functions and direct or indirect participation in disease recovery (8).

Abundant TCR diversity is a prerequisite for broad immunological recognition, and antigen-specific TCRs are an important step in TCR gene transduction-based immunotherapy. Therefore, a clear understanding of TCR structure and diversity generation represents an elementary step in determining the best incorporation of αβ TCRs in disease treatment strategies. Moreover, knowledge regarding TCR bias in different diseases could promote a good prognosis in patients treated via gene transfer. Accordingly, in the present review, we briefly introduce background information regarding TCR structure and diversity. In addition, we summarize recent data concerning TCR selection bias in some diseases, which might serve as a theoretical basis for clinical applications, and thus, further illuminate potential functions in disease treatment.

2. TCR diversity and antigen recognition

The highly variable TCR comprises a number of segments that are encoded by genes at discrete chromosomal locations: the α and γ glycoprotein chains, which comprise V (variable), J (joining) and C (constant) regions and the β and δ chains, which feature an additional D (diversity) region (9). The re-arrangement of V (D) and J through recombination signal sequences (RSS) and the formation of a functional antigen receptor via the activity of the lymphoid-specific protein recombination activating gene (RAG) 1 and RAG 2 exclusively occurs during thymocyte development (Fig. 1). This process involves the random re-arrangement of various V and J genes at the TCR-α locus and V, D and J genes at the TCR-β locus during T-cell development, additional diversity is produced by the random insertion or deletion of >20 non-germline nucleotides at region junctions (V-(N)-J, V-(N)-D and/or D-(N)-J; N represents nucleotide), thus, yielding a TCR recognition spectrum with an estimated theoretical diversity of ~1018 in human (10) and 1015 in mouse (2) although most of those specificities will never be used during an individual's life, as peripheral repertoire in human are composed of 25×106 clonotypes (11) and 2×106 in mouse (1).

Three defined TCR hypervariable regions (CDR1, CDR2 and CDR3) combine to form the TCR antigen-binding site. Crystallographic analysis has revealed that CDR1 and CDR2 interact with a particular MHC molecule, whereas CDR3 interacts with the antigenic peptide bound to the MHC molecule (12,13). Most variation in each chain lies within CDR3, which is responsible for the specific recognition of and interaction with peptide antigens that are presented by MHC molecules. As this region determines the antigen specificity of a T cell, each CDR3 represents a single T-cell clone (14). CDR1α, CDR1β, CDR2α and CDR2β are entirely encoded by the V region in germline DNA segments, whereas CDR3 loops are encoded by the V (D) J junction and the N additions and deletions during the recombination process; relative to CDR1 and CDR2 loops, CDR3 loops are significantly more diverse, and thus, mediate contact between TCR and the antigenic peptide-MHC complex. In addition, the D segment insertion occurs in CDR3 of the TRB/TRD locus, thus, yielding a broader TRB repertoire for antigen recognition compared with TRA and TRG. Whereas the CDR3 loop size distributions of the IgH and L chains and TCR γ and δ chains are relatively broad and dissimilar, in contrast, the CDR3 loop size distribution of the α and β chain are narrow and closely matched, suggesting that a pairing of TCR α and β chains with similar CDR3 loop sizes might be generally required to generate a functional αβ TCR repertoire (14,15). Furthermore, the greater diversity of the CDR3β loop (relative to the CDR3α loop) might indicate that the TCR Vβ chain is the main factor in determining TCR usage bias (16).

As each CDR3 sequence represents one T cell clone, the polyclonal or oligoclonal expansion of T cells can be determined through the detection of CDR3 spectratype by various methods such as PCR DNA blotting, PCR GeneScan sequence analysis, and high throughput TCR sequencing (TCR-seq) (17). The biased TCR AV and BV gene families are considered to be antigen-specific and can be used in immunotherapy.

3. TCR bias in disease

TCR diversity largely remains constant throughout the life span, except in infants and the elderly, because most specificity is generated in the thymus. However, under conditions of antigen exposure, the expansion of specific clonotypes is a common feature of immunity (Table I). Antigen-specific TCRs will demonstrate a preferential usage of particular TCR variable region gene segments, resulting in a TCR spectrum with a ‘skewed’, ‘immunodominant’, ‘restricted’ or ‘limited’ distribution, known as a ‘biased’ repertoire (16). TCR bias can be mainly classified into three types. Type 1 bias is characterised by selecting a single TCR gene family but with obvious diversity in the CDR3 sequences of different individual clones. Type 2 bias refers to the selection of the same amino acid motif in the CDR3 region of an antigen-specific TCR. Type 3 bias indicates a similar spectrum sequence, with differences resulting from different α and β chain pairings. Several factors can influence TCR bias, including thymic selection, the initial immune response, persistent infection and selection of a ‘private’ versus ‘public’ TCR (16).

Table I

Examples of TCR bias in disease.

Table I

Examples of TCR bias in disease.

DiseasesAntigen/antigen peptideMHC restrictionSource of T cellPriority of TCR genesRef.

TRAVTRBV
Tumor
 B-CLLCD42, 3, 5, 6(19)
CD86, 19(19)
PB5(25)
 MelanomaPB6(21)
 DLBCLCD46, 233, 13(28)
PB, TIL13, 23(29)
 CRCCD412, 16,(31)
CD819, 21(31)
PB, TIL12, 16, 19, 21(30)
Infectious disease
 EBVEBNA3(339–347)HLA-B*080126-27(35,43)
EBNA1(407–417)HLA-B*350820, 299(44)
HLA-B*3501
BZLF1(52–64)HLA-B*3508110(45)
 Influenza virusMatrix protein(58–66)HLA-A219(48)
 HIVGag p17(77–85)HLA-A2PB, CD85–6(47)
Env23-1(36)
p24 capsidHLA-B*5703519(39)
 SIVTat(28–35)Mamu-A*01PB, CD8226-5, 14(37)
Gag(181–189)Mamu-A*0113(37)
 Tuberculosis11/38(54)
 Malaria8.1, 8.2(56)
 HCMVpp65(495–503)HLA-A2PB, CD8186-5, 12-4(38)
Autoimmune disease
 SLEPBMC1, 13-1, 15, 16(60,62)
Kidney8, 20(58)
Skin8, 13(59)
Th lines8(61)
 T1DPancreatic islets1, 7, 11, 17, 22(64)
Spleen, PB22(63)
Tumor antigens

T lymphocytes play an effective role in antitumor immune responses (18). Various tumor-associated antigens (TAAs) that are used to discriminate between healthy and malignant tissue have been identified. In addition, antitumor cytotoxic T cells (CTLs), which exist within tumor-infiltrating lymphocyte (TIL) populations and the peripheral blood and generally comprise αβ T cells, have been detected in patients with cancer (19). The overexpression of a restricted TCR gene is a common characteristic of TILs. These proliferating monoclonal T cells, which play a basic role in tumor-specific cellular immune therapy, can be detected and separated using a gene re-arrangement analysis technology.

In some patients with melanoma, the number of T-cell clones of the same TRBV subfamily accounted for >65% of TILs (20,21), and TRBV14 was overexpressed in all patients who were human leukocyte antigen (HLA)-A2 positive but not in patients who were HLA-A2 negative (22,23).

In 1994, Puisieux et al (24) observed that clonally proliferating TCR Vα and TCR Vβ tumor-specific CTLs could kill autologous tumor cells and subsequently transform into specific T-cell clones following isolation and in vitro cultivation. Monoclonal and oligoclonal expansions have been reported in patients with B-cell malignancies (19), and in B-cell chronic lymphocytic leukaemia (B-CLL), an oligoclonally expanded BV19+CD8+ T-cell subset has been demonstrated to specifically react with autologous leukemic B cells (25). TRBV overexpression is more frequently observed in CD4+ T cells than in CD8+ T cells from patients with B-CLL (23), suggesting that leukemic B cells present MHC class II-restricted peptides to CD4+ T cells.

Specific T cells from some patients with myeloma can recognize tumor-derived idiotypic immunoglobulin, and patients with these idiotype-reactive T cells are likely to have a better prognosis (26). No change in TRBV usage was detected between T cells that were cultured in a culture medium alone and with phytohemagglutinin stimulation, suggesting that the tumor-associated antigen-mediated selection of monoclonal and oligoclonal TCR families from stimulated T cells were indeed tumor specific (27). In addition, the clonal expansion of TRBV13 and TRBV23 in CD4+ T cells was identified in patients with diffuse large B-cell lymphoma (DLBCL) (28). Tan et al (29) conducted RT-PCR and GeneScan analysis of the CDR3 repertoires of 29 TRAV and 24 TRBV gene families in PBMCs from patients with DLBCL and identified TRAV and TRBV gene bias.

Using a DNA melting curve method, Zhou et al (30) analysed the CDR3 spectratypes of peripheral blood and TIL from several patients with colorectal cancer (CRC). With respect to the response to CRC antigens, the prominent usage of TRBV16 was observed in peripheral blood T cells, and limited expression of the BV12, 19 and 21 gene families was detected; TILs from patients with CRC exhibited the same phenomena. Although no significant difference was observed between PBMCs and TILs, they found that the ratio of skewed TRBV gene families was higher among TILs than among PBMCs. Although dominant TCR repertoire usage varied among individuals, there is no lack of the same motif, which might imply that different patients can react to the same tumor antigen. Of greater interest is the dissimilarity in CDR3 gene sequences of PBMCs and TILs from the same patients (31). It remains unknown whether the same CDR3 motifs signify PBMCs and TILs that have proliferated in response to the same peptide antigen and whether proliferated PBMCs and/or TILs play a primary role in patients with CRC (30).

Pathogenic infections
Viral infection

Preferential selection of T-cell clones can contribute to the narrowing of an antigen-selected TCR repertoire (32), and such limited TCR repertoires have been observed in some CD8+ T-cell subpopulations (33,34). An increasing number of examples demonstrate the existence of TCR bias in antiviral immunity, and those restricted Vα and Vβ families expression and conserved CDR3 motifs are considered to be immune responders to definitive antigens. Such TCR bias has been observed in response to persistent infections with entities, such as the Epstein-Barr virus (EBV) (35), human immunodeficiency virus (HIV) (36), SIV (37), cytomegalovirus (CMV) (38) and influenza (39). However, this effect of selection is less apparent in the context of non-persistent antigens (16,34). Studies of EBV and CMV infection have demonstrated that TCR bias can result from the prior selection of T cells with high-affinity TCRs (38,40); virus-specific memory CD8+ T cells have been detected in vitro (41).

EBV is a persistent entity that has infected >90% of the population; in this context, biased TCR usage is mainly directed against several EBV antigens (42), and most restricted TCR family members exhibit sequence conservation according to specific antigen epitopes. EBNA1, EBNA3 and BZLF1 are three antigens for which structural data exist (4345). Furthermore, in SIV-infected rhesus macaques, specific clonotypes are associated with protection, and a number of common clonotypes are closely associated with the viral load. Turner et al (16) considered three factors that might determine the constraint of a TCR repertoire during consistent infection: recognition of the peptide-MHC complex, antigen load (higher antigen load = narrower TCR repertoire) and TCR diversity in the naïve pool. In patients with HIV, three so-called ‘protective MHC alleles’ have been identified: HLA-B*57, HLA-B*27 and HLA-B*58. These specific clonotypes are associated with protection and can predict disease prognosis (46,47).

CD8+ T cells are the main population of immune cells that directly act against the pp65 protein (ALV/A2, 495–503) of HCLV, an immunodominant HLA-A2-restricted epitope. ALV/A2-specific T cells exhibited limited clonal diversity and restricted usage of the Vβ regions. The expansion of ALV/A2-specific T cells were observed in response to HCMV activation and/or chronic inflammation, resulting in the selection of a single clonotype with similar public TCR features. High antigen avidity was also observed with ALV/A2-specific clonotypes, further proving that TCR avidity/affinity is the main concern with regard to persistent antigenic stimulation.

During the acute phase of SIV infection, CD8+ T cells respond to the TL8 (TTPESANL; Tat, residues 28–35) and CM9 (CTPYDINQM; Gag, residues 181–189) epitopes that are bound to codominant Mamu-A*01. Although TL8 and CM9 exhibit the same MHC class I restriction, they are associated with different patterns of conserved TRBV gene usage. Whereas TRBV13 usage was restricted in a majority of CM9-specific CD8+ T cells, TRBV14 usage was predominantly observed in TL8-specific CD8+ T cells. A highly conserved CDR3 motif (CASSXXRXSNQPQY) and preferential TRBJ1.5 usage were prevalent among TL8-specific clonotypes. In contrast, no such consensus was evident among CM9-specific CD8+ T cells. Furthermore, TL8-specific subtypes preferred a specific TRAV22 (37).

Conserved usage of the Vα and Vβ sequences were also observed in T cells that were specific for the influenza matrix peptide (5866) (47,48). In addition, the KF11 peptide (KAFSPEVIPMF) is among the immunodominant epitopes that are derived from the p24 capsid peptide of HIV (39,42). A biased TCR repertoire displaying TRAV5 and TRBV19 and sharing common CDR3α and CDR3β sequences was selected.

Tuberculosis

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis, is a well-known common infectious disease (49). As M. tuberculosis is an intracellular bacterium, cell-mediated immunity acts as the driving force during bacterial elimination; in other words, CD4+ and CD8+ T cells play important prophylactic roles against TB (50). The clonal expansion of CD8+ T cells in granuloma lesions and PBMCs has been observed (51,52). In the infected lung, CD4+ T cells have been observed to secrete interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), both of which recruit and activate infected macrophages, thereby killing intracellular TB (53). Similarly, CD8+ T cells also produce IFN-γ and TNF-α and mediate the cytolysis of infected macrophages; in addition, CD8+ T cells can kill M. tuberculosis within macrophages via granule-dependent mechanisms (54). As the CD4+ and CD8+ T cells of patients with TB exhibit decreased levels of functionality, promising therapeutic methods involve promoting an increase in T-cell functionality. Luo et al (54) screened TCR Vα11 and Vβ8 expression in CD4+ T cells and TCR Vα3 and Vβ8 expression in CD8+ T cells because these are specific for a 38-kDa antigen of M. tuberculosis; following transduction into primary CD4+ and CD8+ T cells, these specific genes induced anti-M. tuberculosis activity. Furthermore, the CDR3 spectratypes of two T cell subpopulations were also analysed in 86 patients with different degrees of TB (55), and patients with TB were found to possess a restricted TCR repertoire when compared with healthy controls. A sequence analysis of CDR3 in clonally expanded T cells revealed a highly conserved amino acid motif in both the TCR α and β chains. Severely infected patients exhibited less TCR diversity than did patients with mild disease, suggesting that TCR abundance negatively correlates with disease severity. Furthermore, CDR3 sequence conservation was found to be unrelated to the HLA phenotype; in other words, despite differences in individual HLA phenotypes, common TCR structural features may be observed in associated T cells.

Malaria

Among mice infected with cerebral malaria (CM), those lacking either the αβ or γδ T cells (TCRαβ−/− or TCRγδ−/−) differently manifested the disease. TCRγδ−/− mice were susceptible to CM, whereas TCRαβ−/− mice were resistant. Flow cytometric analysis of peripheral blood lymphocytes revealed that a subset of CD8+ T cells bearing the Vβ8.1 and 2 segments was associated with disease severity (56).

Autoimmune disease

Autoimmune diseases are characterised by tissue damage resulting from an abnormal immune response toward autoantigens. During normal development, positive and negative thymic selection exclude T cells with a low or high affinity for self-MHC; under normal circumstances, the remaining TCRs with moderate self-affinity will not lead to autoimmune disease because of the inhibitory effects of regulatory T cells (Tregs) (57). However, under conditions of genetic vulnerability, many environmental factors can lead to the production of inflammatory cytokines and autoantibodies, which in turn can facilitate disease episodes. Abnormalities in humoral and cellular immunity are likely to be involved in autoimmune disease. Although autoantibodies, which are produced by the humoral immune system, target autoantigens, more recent reports demonstrate the contribution of abnormal T-cell proliferation to the secretion of these aberrant antibodies. As a result, studies concerning abnormal T cell activation address not only the cellular immune component of autoimmunity but also the humoral component.

In patients with SLE, limited expansion of T cells of the TCRβ gene family has been observed in the kidney (58), damaged areas of the skin (59) and peripheral blood (6062). A conserved CDR3 amino acid motif (GGX) has also been detected in PBMCs from 20 patients with SLE. In human patients with type 1 diabetes (T1D), T cells that infiltrate the pancreatic islets mainly express TCRs of the BV gene family, with monoclonal expansion of T cells expressing Vβ1, Vβ7, Vβ11, Vβ17 and Vβ22. A monoclonal expansion of cells expressing Vβ22 with a conserved CDR3 sequence was also observed in the peripheral blood, indicating the homing of circulating cells (63). Zhou et al (64) also analysed αβ TCR distributions in the peripheral blood of patients with T1D, which may be relevant to the onset.

Furthermore, TCR plays a key role in T cell-mediated transplant rejection. Kim et al (65) analysed the TCRβ chain variable gene usage bias in the graft-infiltrating CD8+ T lymphocytes in a human transplanted hand over 178 days, they found the TCR variable gene usage and size distribution revealed the oligoclonality expansion of some TCR gene families. These restricted TCR BV gene are likely to be associated with graft rejection. Aberrant TCR activity has been found to be associated with drug-linked hypersensitivity. Changes in TCR repertoire during treatment correspond with the patients' levels of morbidity (66), thus, a diverse TCR repertoire indicates a healthy condition or good disease outcome.

The tracking of antigen-specific TCRs related to tumors and various pathogenic infections will facilitate an understanding of disease progression. For example, in patients expressing HLA-A2, the CDR3 regions of T cells expressing Vβ17 share the same unique sequence; in contrast, this sequence is difficult to detect in healthy individuals. Another example is TCR-β oligoclonality with respect to autologous stem cell transplantation. Given the differences in TCR repertoire distribution between a healthy and diseased state, oligoclonality can be used as a marker of the degree of tumor cell elimination and the extent of immune reconstitution, and thus, may facilitate the evaluation of treatment efficiency (49). In patients with colorectal cancer, chemotherapy gradually increases the TCR diversity, suggesting favourable prognosis (66). Treating metastatic CRC with bevacizumab combined with modified irinotecan, fluorouracil and leucovorin (mIFL) results in a more normal TCR repertoire than does treatment with mIFL alone (67). All of these changes in repertoire prior to disease onset and after treatment may reflect a relationship between TCR repertoire normalization and relief from disease, and therefore, might indicate the potential diagnostic value of this parameter in a clinical setting (66).

4. Antigen-specific TCR gene transduction

In addition to the various disease treatments that have already been applied in the clinic, including tyrosine inhibitors and monoclonal antibody targeting of tumor-associated surface antigens, and potential suppression of antitumor immune responses, cytokines represent another form of immunotherapy that can modify the outcomes of innate or adaptive immunity, antitumor vaccines and adaptive gene therapies (6878). However, the increased toxicity resulting from cytokine therapy can induce lymphocyte degeneration, reduce TCR repertoire diversity and increase susceptibility to opportunistic pathogens (79). To date, there are three kind of therapies: tumor-infiltrating lymphocytes (CILs), chimeric antigen receptors (CARs) and T cell receptor engineered T cells (80). This kind of transfer of lymphocytes to mediate an effector function is known as adaptive cell transfer (ACT). TILs have been developed with slow but continuing progress (80). Antigen-associated monoclonal TCR Vα and Vβ gene families can be defined according to the length and sequence of the CDR3 region. In vitro experiments have confirmed that following efficient separation and amplification, these specific TCR genes can be incorporated into antitumor or antiviral disease therapy. However, it is difficult to gain a sufficient number of CTLs from the patients' T cell populations, thus, presenting a challenge to the application of this technique. In addition to the limited number of CTLs, immunosuppressive factors might help to downregulate effector T-cell functions. Accordingly, it would be meaningful to study the features and amplification methods that are associated with tumor-specific CTLs because these will play pivotal roles in antitumor adoptive immunotherapy.

All of these factors increase the attractiveness of T cell transduction-based immunotherapy, particularly with regard to long-term survival. The endowment of T cells with high-affinity antigen specificity via TCR transduction has highlighted the growing importance of this effective method with respect to the control and elimination of malignant cells and infectious agents.

Mainstream research has focused on the transduction of tumor or viral antigen-related TCR genes into normal T cells, including mandatory expression of the idiotypic TCR; as a result, the recognition patterns of endogenous TCRs are changed, leading to an increase in cytokine secretion and lethality after a large amplification, an immune response and the generation of the adequate numbers of specific CTLs during treatment. During this process, the TCR repertoires are dynamically monitored before, and for several cycles after therapy, by analysing the CDR3 length distributions within CD4+ and CD8+ T cell subsets. Recently, an in vitro expansion of tumor-specific CTLs was applied with clinical results. These TCR gene-engineered T cells were first used in the clinical treatment of melanoma. The introduction of a MART-1 antigen specific TCR gene into the peripheral blood lymphocytes of patients with melanoma may restore the capacity to resist positive tumor-surface antigens and might completely alter the disease prognosis.

Two methods can facilitate the transfer of exogenous genes into cells: viral vectors or chemical/physical methods (81). Viral vectors like gamma retrovirus and lentivirus enable efficient gene transfer with the least amount of damage; however, viral vectors are expensive, and the process represents a waste of time and resources. In addition, viral vectors cannot deliver large DNA fragments because of package capacity limitations. Furthermore, the potential for widespread viral contamination limits the application of this technique. In comparison, although physical methods, such as electroporation, can induce more cell death, these methods are faster, easier and safer methods of gene transfection, which explains their prominence. In recent years, a more advanced electroporation-based gene transfer method involving nucleofection has been introduced; this method transfers the gene of interest into the nuclei of non-dividing cells, with an high transfection efficiency.

In 1999, CD8+ T cells that were genetically engineered to express the melanoma MART-1-restricted TCRα/β gene exhibited cytotoxicity against HLA-A2-restricted melanoma cells (82). In 2006, the first clinical trial was conducted (83); condition of 2 patients was completely restrained in 15 patients, win 18 months life time without this disease. Many examples of immunotherapy have been reported. The transduction of an HIV-specific TCR gene into patients with HIV-1+ can enhance immunity. In addition, Tang et al (84) recently reviewed the mechanism by which the tumor microenvironment (TME) affects the efficiency of immunotherapy and how to best use TME as a contributor to immunotherapy. However, this kind of introduction of exogenous TCR gene may lead to mispairing of the endogenous TCR subunits with introduced TCR chain, which may alter the TCR specificity of antigen recognition, not only lead to the loss of antitumor, but also the formation of autoreactive T cells (8587). Hu et al (91) have shown the humanized mouse (hu-mouse) model which transplantation of human fetal thymus tissue and CD34+ fetal liver cells into immunodeficient mice, leading to the development of human lymphohematopoietic cells and the formation of secondary lymphoid organs (8890). They used this hu-mouse model to generate melanoma antigen (MART-1) specific human T cells for studies of human cancer immunotherapy. They found that MART-1 specific T cells can be generated after transduction of lentiviruses containing MART-1 specific TCR gene, implying that it was possible to produce large quantity of MART-1 specific T cells with antitumor activity.

The third and a powerful new immunotherapeutic approach intended to target TAAs comprises chimeric antigen receptors (CARs), which comprise an extracellular region - the antigen-binding domain of a monoclonal antibody (containing the variable domains of the light and heavy chains), a stem-like region, a transmembrane region and the intracellular signalling portion of a T-cell receptor, can combine the specificity and effectiveness of a monoclonal antibody with the cytotoxic effects and long-term persistence of CTLs (92), thus, it can make it possible to endow immune system with reactivity and add benefits which can be seen with cytotoxic chemotherapy or targeted therapy of the rapid onset of action. This method has been proven safe and effective for the induction of tumor remission in patients with neuroblastoma (93) and hematological malignancies (94). To date, the most successful CARs were those specific for CD19 on B cell malignances (92). Several research centres have confirmed the compelling efficacy of CARs against acute and chronic B-cell malignancies (95).

Compared with TCRs, there are several different parameters. First of all, these two format receptors target different antigens, TCRs react to natural ligands with MHC restriction, and it is necessary to enhance the affinity of the TCR with specific peptide-MHC in order to mediate the activities of T cells against the peptide-MHC antigen during the process of adoptive T cell therapy. In contrast, CARs are not MHC-dependent, and can function both in CD4+ and CD8+ T cells. Furthermore, CARs can induce activity even against low-density antigens. The CAR density, antigen-binding domain affinity still need to be optimized to match the antigen density of tumor and tissue (92). However, risk also exits because both on-target and off-target recognition of normal tissue occur in engineered T cells. For instance, in patients treated with carcino-embryonic antigen specific TCR modified T cells showed on-target toxicity, resulting in inflammatory colitis in normal colon (96). Apart from toxicity, both TCR and CARs will give rise to autoimmunity and inflammation from the infusion of ex vivo activated autologous lymphocytes. However, the incidence can be calculated to be less than one in 1,000 patients, which is lower than cytotoxic chemotherapy (97). A common challenge to all therapies, including antigen specific TCR gene based therapy, is to develop cost-effective, and efficient manufacturing and delivery capabilities (80).

5. Conclusions

Gene re-arrangement during the thymic development of T cells introduces sufficient TCR diversity to meet the varied requirements for antigen recognition. Over the last two decades, considerable research has demonstrated a close relationship between TCR diversity and immune responses against various antigens. Under natural conditions, the TCR repertoire is diverse and exhibits a Gaussian distribution, and the CDR3 of each gene family is represented by at least eight different lengths. As each CDR3 sequence represents a specific T-cell clone, CDR3 region spectratyping can reflect TCR clonality, and antigen-specific TCRs can be selected for immunotherapeutic use. A basic understanding of the T-cell receptor structure and recombination mechanisms can help us to understand the aetiology of TCR diversity and thus identify antigens.

An analysis of TCR bias in tumor, pathogenic infection, autoimmune disease and other disease settings is a basic prerequisite to a deep understanding of the immune mechanisms underlying antigen-specific responses and specific immunotherapy. Many studies have described how TCR abundance might be affected by certain infections, malignancies and immune dysfunctions. A broader specific peptide-MHC complex repertoire can help to reduce the emergence of a persistent viral infection. Three factors, thymic selection, initial immune response and persistent infection, are all known to influence specific TCR selection. In addition, some pathologies can induce the appearance of specific TCR clonotypes, which might be useful as immunological markers in clinical settings.

An understanding of T-cell responses against specific antigens is particularly important with respect to adaptive immunity. The immunotherapeutic role of αβ T cells has been strongly focused on their function in recovery from disease. In contrast, how would one capture the ideal TCR? It is necessary to monitor CDR3 spectratypes and conserved amino acid motifs. In addition to several above mentioned common methods, nascent high-throughput sequencing (TCR-seq) using next-generation sequencing also provides new insights to the sequence analysis of TCR repertoires under conditions of health and disease. The transduction of specific TCR genes with conserved CDR3 motifs into normal T cells can alter the original identification model and form antigen-specific T cells; this approach to disease treatment has yielded results that could further enhance the likelihood of survival. However, new strategies and methods still need be developed to enhance specific recognition between TCRs and antigens, with the aim of improving immunotherapeutic approaches to persistent infection and cancer.

Acknowledgements

The authors appreciate the support of the National Natural Science Funds (nos. 31372423 and 31302072) from the National Natural Science Foundation of China.

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Wang C, Yu P, He X, Fang Y, Cheng W and Jing Z: αβ T-cell receptor bias in disease and therapy (Review). Int J Oncol 48: 2247-2256, 2016
APA
Wang, C., Yu, P., He, X., Fang, Y., Cheng, W., & Jing, Z. (2016). αβ T-cell receptor bias in disease and therapy (Review). International Journal of Oncology, 48, 2247-2256. https://doi.org/10.3892/ijo.2016.3492
MLA
Wang, C., Yu, P., He, X., Fang, Y., Cheng, W., Jing, Z."αβ T-cell receptor bias in disease and therapy (Review)". International Journal of Oncology 48.6 (2016): 2247-2256.
Chicago
Wang, C., Yu, P., He, X., Fang, Y., Cheng, W., Jing, Z."αβ T-cell receptor bias in disease and therapy (Review)". International Journal of Oncology 48, no. 6 (2016): 2247-2256. https://doi.org/10.3892/ijo.2016.3492