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. 2019 May 17;76(14):2779–2788. doi: 10.1007/s00018-019-03117-1

Progress on chicken T cell immunity to viruses

Manman Dai 1,3, Chenggang Xu 1,3,4,5, Weisan Chen 2,✉, Ming Liao 1,3,4,5,✉
PMCID: PMC11105491  PMID: 31101935

Abstract

Avian virus infection remains one of the most important threats to the poultry industry. Pathogens such as avian influenza virus (AIV), avian infectious bronchitis virus (IBV), and infectious bursal disease virus (IBDV) are normally controlled by antibodies specific for surface proteins and cellular immune responses. However, standard vaccines aimed at inducing neutralizing antibodies must be administered annually and can be rendered ineffective because immune-selective pressure results in the continuous mutation of viral surface proteins of different strains circulating from year to year. Chicken T cells have been shown to play a crucial role in fighting virus infection, offering lasting and cross-strain protection, and offer the potential for developing universal vaccines. This review provides an overview of our current knowledge of chicken T cell immunity to viruses. More importantly, we point out the limitations and barriers of current research and a potential direction for future studies.

Keywords: Chicken, CD8+ T cell response, CD4+ T cell response, Virus, Epitope

Introduction

It is well known that avian-related viruses such as avian influenza virus (AIV), Newcastle disease virus (NDV), avian infectious bronchitis virus (IBV), and infectious bursal disease virus (IBDV) have been causing enormous economic losses in the global poultry industry. Although vaccines have been used for a long time to prevent epidemics in China, these viruses have still been identified and found to induce disease in livestock in recent years [1–4]. The protection provided by commercial vaccines, such as inactivated influenza vaccines, is largely dependent on stimulated neutralizing antibodies, which directly bind to the virus to prevent its entry into host cells [5]. As immune-selective pressure results in the continuous mutation of viral surface proteins, the protective effects of such vaccines against current or upcoming epidemic strains can be significantly decreased.

Vaccines aimed at stimulating T cell responses are currently the subject of intense interest for mammalian studies because they promise both broader strain coverage and longer-lasting protection than current antibody-based vaccines. Therefore, it may also be possible to develop safe and more effective T cell-based vaccines for the poultry industry in the future.

Here, we summarize the published data and provide an overview of progress in understanding chicken T cell immunity against the above-mentioned viruses. In addition, this review aims to highlight the limitations and barriers of current research and a potential direction for future studies.

T cell response

T cells proliferate and differentiate into effector T cells after recognizing an antigen on the surface of an antigen-presenting cell (APC), in the context of major histocompatibility complex (MHC) molecules and costimulation. The recognition of cognate antigen–MHC complexes by T cells requires a “second signal” generated via numerous costimulatory and inhibitory receptors to regulate the extent, quality, and duration of their activation. Structurally, these receptors consist of the immunoglobulin super family (IgSF) and tumor necrosis factor (TNF) family members. Some costimulatory and inhibitory receptor ligand pairs have been characterized in chickens (Table 1), but thus far the vast majority have not been analyzed. Interestingly, the activating receptor CD28 and the inhibitory receptor CTLA-4 bind to identical ligands designated as CD80 and CD86, but deliver opposing signals. Triggering CD28 leads to T cell activation, whereas CTLA-4 ligation inhibits further T cell activation and promotes T cell tolerance [6].

Table 1.

Chicken costimulatory molecules

Function Family Receptor Ligand References
Activating IgSF CD28 (chr.7) CD80/86 [6, 7]
Activating IgSF ICOS (chr.7) Y08823 [6, 7]
Inhibitory IgSF CTLA-4 (chr.7) CD80/86 [6, 7]
Inhibitory IgSF PD1 (chr.9) ? [6, 7]
Activating TNFR CD30 (chr.21) CD30L [8, 9]
Activating TNFR RANK/0PG(chr.2) RANKL [10]
Activating TNFR CD40(chr.20) CD40L [11]
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CD8+ T cells

Peptides derived from endogenous antigen processing are loaded on to MHC class I molecules. Almost all nucleated cells express class I heterodimer molecules on their surface and make use of the specialized MHC peptide binding cleft to display peptides derived from tumor and pathogen antigens, mostly from intracellular locations. CD8+ T cells first recognize the peptide–MHC class I complex via the T cell receptor (TCR), and then proliferate and differentiate into armed antigen-specific cytotoxic T lymphocytes (CTLs). Activated CTLs are able to kill other cells displaying the same peptide–MHC complex. CTLs exert their protective effect via a range of effector mechanisms, including the release of cytotoxic granules that contain perforin and granzymes and the induction of apoptosis via Fas/Fas-L interactions, and via TNF-related apoptosis-inducing ligands and the production of various pro-inflammatory cytokines, including interferon gamma (IFN-γ), macrophage inflammatory protein-1β, interleukin (IL)-2, and TNF-α, which can either directly inhibit viral function or help recruit other immune cells to assist with viral clearance [12, 13]. In this manner, infected cells are eliminated, thereby limiting the replication and spread of invading pathogens. Based on detection of the gene transcription levels of cytolytic molecules in the immune organ, chicken CD8+ T cells are thought to use the Fas/Fas-L and/or perforin–granzyme A cytolytic pathways to clear viruses, such as IBDV, IBV and Marek’s disease virus (MDV) [14–17]. The cytotoxic activity of CTLs has been detected in response to MDV-infected splenocytes and cell lines expressing MDV antigens [18]. However, still very few researchers have further studied the potential mechanisms of specific chicken CD8+ T cell responses to virus infection in vitro via monitoring CTL activity, which is a more accurate method, because this assay is expensive, technically challenging, and requires the use of inbred chickens and MHC-matched target cells.

CD4+ T cells

MHC class II molecules are mainly expressed on the surface of APCs such as macrophages, dendritic cells (DC), and B cells. Exogenous antigens derived from pathogens can be endocytosed or phagocytosed and processed by APCs, and the resulting peptides are presented on the surface of the APC in the context of MHC class II molecules. CD4+ T cells recognize the peptide–MHC-II complex via their TCRs and then exert their protective effect indirectly by “helping” both CD8+ T cells and B cells to eliminate virus and virus-infected cells via cytotoxic and antibody neutralization mechanisms, respectively, although some CD4+ T cells are capable of direct killing [19–21]. For example, CD4+ T cells expressing the cytolytic molecule perforin were detected in IBDV-infected chickens [15]. Effector CD4+ T cells can differentiate into many T helper (Th) subsets, resulting in the production of different cytokine patterns and effector functions. The development of various effector subsets is largely determined by cytokines present during CD4+ T cell priming. The two best characterized effector subsets are Th1, promoted by IL-12 and IFN-γ and inhibited by IL-4, and Th2, promoted by IL-4 and suppressed by IFN-γ. Cytotoxic Th1 cells produce the “signature” cytokines IL-2, IFN-γ, and TNF-α, and Th2 cells produce the “signature” cytokines IL-4, IL-5, IL-13 and IL-10, which that are crucial for regulating immune responses to intra- and extracellular pathogens, respectively [22, 23]. The existence of the Th1–Th2 paradigm in chickens has also been known [24]. However, whether this paradigm holds true at the cellular and molecular levels and whether chicken Th cells can become terminally polarized to a Th1 or Th2 phenotype remain to be determined. Additionally, chicken CD4+ T cells can be polarized into Th17 cells that produce IL-17A, as determined by genomic analyses [25], infectious studies [26], and phenotype analyses [27, 28]. Additionally, two subpopulations of chicken regulatory T cells (Treg cells) have been identified including TGF-beta+CD4+ T cells and CD4+CD25+ T cells [29, 30]. Chicken CD4+CD25+ Treg cells have been shown to express high level of CTLA-4, produce high concentrations of IL-10, TGF-β4, and suppress T cell proliferation in vitro [29]. Chicken TGF-beta+ Treg cells are reportedly involved in the pathogenesis and immunosuppression of MDV infection [30].

Limitations of studying chicken CD4+ and CD8+ T cell responses

Our knowledge of T cell immunity stems mainly from human and mouse studies, and avian species have their own unique characteristics. Until recently, the majority of studies on the avian T cell response were limited to detecting the proliferation of splenocytes and IFN-γ production due to limited reagent availabilities, detection method, and T cell culture techniques [31–33]. In addition, the lack of an appropriate mAb against chicken cytokines has also hampered the phenotypic and functional identification of chicken T cells. As shown in Table 2, technologies of intracellular cytokine staining (ICS) and T cell line generation have been rarely established and used in chicken T cell immunity research due to limited reagent availability, which prohibits studies on the chicken T cell phenotype, and dominant viral antigen and epitope identification. The current bottleneck regarding our knowledge of chicken CD4+ and CD8+ T cell responses at the cellular and molecular levels must be surpassed.

Table 2.

Major methods of detecting T cell responses used in research on mammals and chickens

Species Method Purpose References
Mammal CD107 assay CTL function degranulation [34]
Mammal IFN-γ-secreting ELISPOT assay T cell activation [35]
Mammal ICS assay CD4+ and CD8+ T cell enumeration and phenotype [35, 36]
Mammal Generation of virus- or peptide-specific T cell line Dominant viral antigen or minimal T cell epitope identification [35, 37]
Chicken Cr release assay CTL killing [18]
Chicken IFN-γ-secreting ELISPOT assay Splenic lymphocyte response [38]
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Chicken MHC

Compared to the mammalian MHC, the chicken MHC, also called the “B locus”, is more compact and organized differently. The B-F/B-L region within the B locus contains the genes encoding classical class I and class IIβ chains, which present antigens to stimulate immune responses, such as allograft rejection, antiviral and antitumoral immunity, and cellular help for high affinity antibody production [39–43]. Peptide binding motifs have been discovered for a number of common chicken MHC class I alleles (Table 3). The anchor residues involved in binding to the MHC class I molecules of these different alleles were found to be just as fastidious as those described for mammalian MHC class I molecules [39, 44, 45]. Regretfully, there have been no studies on the structure or peptide binding motifs of chicken MHC class II molecules to date. There are several reports showing that chicken MHC class II molecules determine the responses to the inactivated vaccines tested, which might be largely related to stimulation by the binding epitopes [46–49]. Therefore, to better understand the role of chicken MHC class II molecules during virus infection, it is critical to conduct side-by-side structural and functional studies on these molecules.

Table 3.

Known peptide binding motifs for chicken class I molecules [32]

MHC class I allele Anchor residues
MHC B12 X–X-X–X-V/I-X-X-(X)-V/L/I
MHC B4 X-D/E-X-X-D/E-X-X-(X)-E/L/I
MHC B15 X-R-X–X-X–X-X-(X)-Y
MHC B19 X-R-X–X-X–X-X–Y/P/L/F
MHC B21 X–H/K/R-X-X–X-X–X-(X)-E/D-X-A/V/L/I/F/M
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X represents any amino acids. Anchor residues specific for the different MHC alleles are shown in bold. ‘/’ indicates that either one of the amino acids could be chosen. ‘(X)’ represents a variable number of amino acids between the anchor residues.

In chickens, two types of class I and class II genes exist; class I genes include the BF2 and BF1 genes, meanwhile class II genes consist of the BLB2 and BLB1 gene. However, it seems most likely that there will be a single dominantly expressed class I (BF2) and class II molecule (BLB2) on the surface of chicken cells, which determines either resistance or susceptibility to a particular pathogen [50]. The peptide binding motifs shown above could therefore potentially be used to predict the corresponding MHC-determined resistance and susceptibility. Chicken MHC B haplotypes have been shown to display differential resistance to several viruses, including Marek’s disease virus, avian leukosis virus, NDV, Rous sarcoma virus (RSV), IBV, and avian influenza virus (AIV), as well as Salmonella [51–60]. This phenomenon is most likely related to the neutralizing antibody and CD4+ and CD8+ T cell responses stimulated by viral peptides presented by specific MHC B alleles. However, in contrast to what has been described for humans and mice, knowledge of virus epitope-specific CD4+ and CD8+ T cells in chickens is limited.

Importance of T cell immunity in avian virus infection

In avian virus infection, animal studies clearly indicate a protective role for CD8+ T cells, as summarized in Table 4. For instance, CD8+ T cells can eliminate infectious viruses such as IBV, RSV, and AIV [38, 61, 62]. Moreover, adoptive transfer of activated H9N2 AIV-specific CD8+ T cells into naïve chickens reduced morbidity and enhanced survival following subsequent lethal H5N2 AIV challenge [63, 64]. The latter studies are particularly important because they demonstrate that memory CD8+ T cells protect against AIV and therefore provide a direct rationale for the development of T cell-based vaccines that elicit cross-protective CD8+ T cells with the potential to combat novel AIV strains whose surface hemagglutinin glycoproteins are not recognized by pre-existing antibodies.

Table 4.

Relevant publications showing that CD8+ T cells are important in avian virus infection

Key observation Model Experimental design Major findings Method of detection References
CD8+ T cell epitopes were effective against IBV challenge Specific pathogen-free (SPF) chickens 1. Spleen lymphocytes from SPF chickens immunized with the S1 protein were stimulated by synthesized peptides and reactivity was tested Four peptides efficiently stimulated CD8+ T cell proliferation and IFN-γ secretion ELISpot assay and flow cytometry [38]
2. Chickens were vaccinated with the poly-CTL-epitope DNA vaccine (pV-S1T), and the protection efficacy was analyzed Ninety percent of immunized chickens were protected after challenge with 106 ELD50 of IBV. Survival
CD8+ T cell epitope from v-Src is immunoprotective against Rous sarcoma virus growth Chickens with MHC class I allele B-F12 Chickens were vaccinated with peptides in liposomes. T cell proliferation was detected in vitro and protection efficacy was analyzed in vivo The tumor incidence in immunized chickens was reduced from 100% to 55.6% after challenge with PR-RSV-C [3H] thymidine uptake assay, flow cytometry and tumor incidence [61]
Cross-reactive cellular immunity induced by H9N2 influenza viruses protected chickens from lethal infection with H5N1 influenza viruses B2 syngeneic SPF chickens (B2/B2) Adoptive transfer of T lymphocytes or CD8+ T cells from H9N2-infected chickens protected naïve chickens from lethal H5N1 influenza virus Most chickens primed with H9N2 survived lethal challenge; H5N1- and H9N2- specific CD8+ T cells recognized target cells infected with H5N1 Flow cytometry and CTL assay [63, 64]
T cells primed with H9N2 can react to homologous (H9N2) and heterologous (H7N2) AIV-infected target cells B2 syngeneic SPF chickens (B2/B2) Splenic lymphocytes from infected and naïve birds were examined for cross-reactivity against homologous and heterologous low pathogenic avian influenza (LPAIV) infection by ex vivo stimulation Splenic lymphocytes derived from H9N2-infected birds displayed lysis of both homologous and heterologous isolates of AIV- infected target cells CTL and proliferation assays [62]
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Data for chicken CD4+ T cells are almost nonexistent compared to those for their CD8+ counterparts in the context of AIV, IBV, and IBD infection, but they are nevertheless important. A key period for developing immunosuppression of avian leukosis virus subgroup J (ALV-J) infection was identified at 3–4 weeks post-infection, when CD4+ T cell numbers were significantly reduced [65]. In additon, a potential vaccine for ALV-J has been reported to increase the numbers of CD4+ and CD8+ T cells as well as the IL-4 and IFN-γ levels in immunized chickens [66]. Moreover, chicken biliary exosomes significantly inhibited ALV-J replication while promoting the proliferation of CD4+ T cells [67]. Therefore, these findings imply that CD4+ T cells mediate protection against ALV-J.

Taken together, these studies highlight the importance of CD4+ and CD8+ T cells in avian virus infection and strongly suggest that an optimal T cell-based vaccine needs to induce both protective CD4+ and CD8+ T cells.

Known chicken CD4+ and CD8+ T cell epitopes

To date, 22 CD8+ T cell epitopes and one CD4+ T cell epitope for AIV, five CD8+ T cell epitopes and 10 CD4+ T cell epitopes for IBV, one CD8+ T cell epitope for IBD, and one CD8+ T cell epitope for RSV have been identified according to the Immune Epitope Database (IEDB, http://www.iedb.com, see Table 5).

Table 5.

Source antigens of the chicken T cell epitopes recorded in IEDB

Virus Source antigens CD8+ T cell epitopes (n) CD4+ Tcell epitopes (n)
AIV Hemagglutinin 2 1
Nucleocapsid protein 2 0
Nucleoprotein 13 0
Matrix 5 0
Total 22 1
IBV S1 glycoprotein 5 5
S2 protein 0 1
Nucleocapsid protein 0 4
Total 5 10
IBD VP2 1 0
RSV v-src 1 0
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The published minimal CD8+ T cell and CD4+ T cell epitopes, including those from all linked references in the IEDB, are listed in Tables 6 and 7, respectively. In Table 6, four CD8+ T cell epitopes derived from IBV and one CD8+ T cell epitope derived from RSV have been identified against viral infection by animal experimentations [38, 61],and the detailed information is shown in Table 4. Besides, one CD8+ T cell epitope derived from IBDV was verified that conferred protection to IBDV challenge, as assessed by bursal damage and viremia [68]. In ex vivo functional verification experimentations, 21 CD8+ T cell epitopes in AIV including H5N8, H5N1, and H7N1 subtypes and one CD8+ T cell epitope in IBV (NQFYIKLT) were found to stimulate the activation of avian lymphocytes [31, 32, 69–71]. However, one CD8+ T cell epitope in H9N2 AIV (KILTIYSTV) has just been identified via binding detection analysis instead of functional experiments. In Table 7, the CD4+ T cell epitope derived from AIV (WTILKPSDTINFESN) has been identified to induce CD4+ T cell activation [31]. But, the CD4+ T cell epitopes derived from IBV need to be further identified by modern and more accurate methods.

Table 6.

Chicken minimal CD8+ T cell epitopes recorded in IEDB

Virus Antigen Epitope sequence Position MHC restriction References
Influenza A virus (A/chicken/Guangdong/11/97(H9N2)) Hemagglutinin KILTIYSTV 523–531 BF2*2101 [75]
Influenza A virus (A/turkey/Ireland/1378/1983(H5N8)) Hemagglutinin WTILKPSDTINFESN 246–260 chicken class I [31]
Influenza A virus (A/goose/Guangdong/1/1996(H5N1)) Nucleocapsid protein KRGINDRNF 198–206 B19 [69]
Influenza A virus (A/goose/Guangdong/1/1996(H5N1)) Nucleocapsid protein PKKTGGPIY 89–97 B19 [69]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein VMELIRMI 189–196 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein AVKGVGTMV 181–189 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein DGKWVRELI 100–108 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein EDLRVSSFI 338–346 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein AEIEDLIFL 250–258 B4 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein NATEIRASV 20–28 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein PTFSVQRNL 409–417 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein VERMVGGI 28–35 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein VGTMVMEL 185–192 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein VGTMVMELI 185–193 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein YDKEEIRRI 110–118 B4 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Nucleoprotein YEQMETGE 10–17 B4 [32]
Influenza A virus (A/goose/Gongdong/1/96 (H5N1)) Nucleoprotein RRRDGKWV 69–76 BF2*1501 [70]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Matrix KTRPILSPL 47–55 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Matrix ILGFVFTL 59–66 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Matrix VETYVLSI 7–14 B12 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Matrix MRTIGTHP 216–223 B19 [32]
Influenza A virus (A/chicken/Italy/1067/1999(H7N1)) Matrix KDDLIENL 230–237 B12 [32]
Avian infectious bronchitis virus (strain Holte) S1 glycoprotein GAYAVVNV 45–52 Chicken class I [38]
Infectious bronchitis virus Spike glycoprotein S1 subunit, partial SRIQTATDP 412–420 Chicken class I [38]
Avian infectious bronchitis virus (strain Holte) Spike glycoprotein S1, partial SRIQTATQP 413–421 Chicken class I [38]
Infectious bronchitis virus S1 glycoprotein, partial SRNATGSQP 516–524 Chicken class I [38]
Infectious bronchitis virus S1 glycoprotein NQFYIKLT 527–534 Chicken class I [71]
Infectious bursal disease virus 52/70 VP2 GNVLVGEGV 156–164 BF2*1201 [68]
Rous sarcoma virus v-src LPACVLEV 517–524 B12 [61]
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Table 7.

Chicken minimal CD4+ T cell epitopes recorded in IEDB

Virus Antigen Epitope sequence Position MHC restriction References
Avian infectious bronchitis virus (strain Vic S) S1 glycoprotein KAVSAAGVHFKAGGPI 186–201 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) S1 glycoprotein ITYKVMREVRALAYFVNGTA 201–220 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) S1 glycoprotein QYNTGNFSDGLYPFTN 237–252 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) S1 glycoprotein PPNSGGVNTIQLYQTKTAQ 286–304 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) S1 glycoprotein GSQAIENQFYIKLTNGS 521–537 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) S2 protein NCPYVSYGKFCIKPDGSIST 8–27 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) Nucleocapsid protein GYWRRQARYKPGKSG 69–83 Chicken class II [76]
Avian infectious bronchitis virus (strain Vic S) Nucleocapsid protein PAADLNWGENQDGIVWV 100–116 Chicken class II [76]
Avian infectious bronchitis virus (strain M41) Nucleocapsid protein QHGYWRRQARFKPGKGG 67–83 Chicken class II [77]
Avian infectious bronchitis virus (strain M41) Nucleocapsid protein WRRQARFKPGKGG 71–83 Chicken class II [77]
Influenza A virus (A/turkey/Ireland/1378/1983(H5N8)) Hemagglutinin WTILKPSDTINFESN 246–260 Chicken class II [31]
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Almost all these epitopes were pre-screened via either the peptide elution-based method or peptide prediction algorithms. The elution-based method identifies epitopes by eluting peptides from MHC complexes and analyzing them via sequencing, mass spectrometry, or both. Although it works well for identifying many peptide sequences, the peptide elution-based method does not indicate whether a particular peptide is actually immunogenic. Peptide prediction algorithms assign the likelihood of a particular peptide being presented by an MHC molecule based on the peptide sequence and known MHC binding motifs. However, given the polymorphism of MHC alleles and the fact that many immunogenic peptides do not even contain typical binding motifs, this method could be fallible, does not predict epitopes that could possibly be post-translationally modified, and is unable to predict immunodominant epitopes [12]. In addition, the above chicken T cell epitope functional verification assay is limited to detecting the peptide-stimulated lymphocyte proliferation or IFN-γ production determined by the IFN-γ ELISPOT assay. Detailed information about these detection methods is described in “T cell response” and is listed in Table 2.

Furthermore, researchers do not systematically identify peptides from each viral protein. In fact, targeted efforts to identify T cell epitopes derived from partial viral proteins might have biased antigen selection. For example, some researchers might have initially stereotypically thought that the HA protein of influenza A virus (IAV) might be the dominant target of the CD4+ T cell response. However, M1 and NP were reported to be dominant antigens recognized by IAV-specific CD4+ T cells after screening 11 individual IAV proteins in humans [37, 72]. Interestingly, in chicken studies, AIV HA protein is still chosen, often the only antigen, for identifying CD4+ T cell epitopes as shown in Table 5.

A systematic screening approach using antigen-specific T cells is a more accurate and robust method for identifying immunodominant peptides [73, 74]. This approach identifies highly immunogenic peptides with different MHC combinations and provides the most direct and accurate identification of potentially useful vaccine candidates. In the future, we believe that this method could potentially be used to identify immunodominant epitopes recognized by chicken T cells. The main barriers to this effort are the culture of chicken antigen-specific T cells in vitro and the establishment of infection models for the analysis of T cell function in vivo. Researchers should commit to breaking these technical barriers to allow future discoveries in the field of chicken T cell research. For instance, researchers need to identify the phenotypes and functions of various types of chicken T cells, the dominant viral antigens, and the minimal epitopes to establish a chicken T cell epitope database.

Concluding remarks

Avian T cell immunity plays an important protective role against avian virus infection, and T cell-based vaccines represent an important new development in worldwide efforts to combat virus infection. However, research on avian T cell immunity is still in its infancy. A few areas of the avian virus-specific T cell response remain unknown, especially the identification of immunodominant T cell epitopes. Therefore, we summarized comprehensive information from previous studies and highlighted a potential direction for future studies. Particularly, an urgent need exists for the development of major tools, including different kinds of antibodies for intracellular cytokine staining, various APC lines expressing different MHC alleles, in vitro culture methods to maintain chicken T cell lines or even T cell clones, infection models for the analysis of T cell function in vivo, and immune evasion mechanisms.

Mammalian studies indicate that T cell-based vaccines might have the potential to be universal vaccines and address the limitations of antibody-based approaches concerning broader virus strain protection [12]. Additionally, in chicken studies, H9N2 AIV-specific T cells could reportedly provide cross-protection against heterogenous H9N2 and H5N2 AIV infection [63, 64, 78], implying that chicken T cell-based vaccines eliciting cross-protective T cell responses could potentially combat various AIV strains, especially novel strains whose surface hemagglutinin glycoproteins are not recognized by pre-existing antibodies. In addition, the future implementation of T cell-based universal vaccines is likely beneficial for decreasing the usage of different vaccine subtypes in livestock, reducing stress to the animals, and lowering labor and production costs. However, it should be noted that vaccine, especially live vaccine, usage may induce silent infection, thus perpetuating the disease [79]. In general, chicken T cell-based vaccines would be the research and development trend of future vaccines.

Based on the limited reference availability, we have summarized the chicken T cell immunity against common avian viruses in this review to assist in further studies. We hope that a better understanding of avian T cell immunity will enable researchers in the field to develop future vaccines capable of stimulating a wider range of CD8+ and CD4+ T cell responses.

Author contributions

MMD drafted the manuscript. WSC, ML, and CGX revised the manuscript.

Funding

This work was supported by the National Natural Science Foundation Grants (31802174 and 31830097) and a China Postdoctoral Science Foundation Grant (2018M630956).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of financial interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Weisan Chen, Phone: +61394793961, Email: Weisan.Chen@latrobe.edu.au.

Ming Liao, Phone: (86)20-85280240, Email: mliao@scau.edu.cn.

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