The immune system protects against disease by recognizing invading pathogens, such as bacteria and viruses, and launching various responses to eliminate them. In vertebrates, such as mice and humans, this response often involves both an ‘innate’ and an ‘adaptive’ component. The innate immune response is fast but it is not targeted at the specific pathogen that needs to be eliminated. The adaptive immune response is slower, but it is also stronger and tailored to combat the specific pathogen that is attacking the host. In general, both the innate and adaptive immune responses work together to combat the infection.

The innate immune system is activated when host cells are damaged or stressed, or when ‘foreign’ molecules that are tell-tale signs of microbes and pathogens are detected. It enlists white blood cells that engulf and digest infected host cells or pathogens, and then display the digested fragments via proteins called major histocompatibility complexes. The adaptive immune response relies on other white blood cells called B cells (which make antibodies) and T cells (which carry out a variety of roles).

Each T cell will respond to a very specific fragment of protein displayed by a major histocompatibility complex. Although a bacteria or virus can generate thousands of protein fragments, only a select few will stimulate an immune response. This phenomenon is known as immunodominance.

As T cells mature in the thymus—a specialized organ located in the chest—they undergo both positive and negative selection. To survive positive selection, the T cells must be able to recognize fragments from the host’s own proteins. Negative selection removes T cells that interact too strongly with these ‘self-peptides’ because such interactions will cause the T cells to destroy the host’s tissues and cause auto-immune diseases. Positive selection is thought to have an important role in immunodominance because it shapes the population of T cells released from the thymus, but it has been difficult to test this hypothesis.

Now Lo et al. have explored this question by engineering transgenic mice in which gp250—a self peptide that positively selects T cells that respond to a foreign protein called MCC—was the only self peptide to be presented during positive selection. Subsequent experiments showed that the mature T cells released by the thymus increased the fraction of T cells that were capable of responding to the dominant fraction of possible MCC fragments. By establishing a clear connection between positive selection and immunodominance, the work of Lo et al. could assist the development of more effective vaccines.

An individual pathogen encodes thousands of potentially immunogenic epitopes, yet during the course of an infection, generally only a fraction of epitopes actually stimulate T cell response (Sercarz et al., 1993; Sant et al., 2007; Weaver and Sant, 2009; Jenkins et al., 2010). This fundamental feature of T cell responses is known as immunodominance (Sercarz et al., 1993; Chen et al., 2001; Yewdell and Del Val, 2004; Yewdell, 2006; Sant et al., 2007; Weaver and Sant, 2009; Jenkins and Moon, 2012). Most of the effort in immunodominance studies has focused on the antigen presentation and processing pathways (Deng et al., 1993; van Ham et al., 1996; Nanda and Sant, 2000; Chen et al., 2001; Crowe et al., 2003; Chen and McCluskey, 2006; Lazarski et al., 2006; Yewdell, 2006; Weaver and Sant, 2009). Yet immunodominance is also defined by the frequencies of naive T cells specific for individual antigens (Kotturi et al., 2008; Jenkins and Moon, 2012; Kwok et al., 2012). Given that thymic positive selection serves as a major developmental process to generate mature T cell repertoires (Jameson et al., 1995; Morris and Allen, 2012), one may reason positive selection would play a role in determining naive T cell precursor frequency to dictate immunodominance. However, this possibility has been difficult to address directly, due to several technological issues. First, the frequency of T cells specific for individual peptide–MHC ligands is at most about 20–100 cells per million naive T cells (Jenkins and Moon, 2012), making it difficult to identify such an infrequent population. Second, to directly test the potential role of positive selection in immunodominance requires the knowledge of what T cell population specific for a defined antigen a positively selecting ligand is capable of selecting. Therefore, the low frequency of naive T cell precursor and the ignorance of essential information have limited the examination of the roles of positive selecting ligands in dictating naive T cell precursor frequency and immunodominance.

The murine CD4⁺ T cell response against cytochrome c is an outstanding model system to investigate the impact of positively selecting ligands on immunodominance (Solinger et al., 1979; Schwartz, 1985; Engel and Hedrick, 1988). Only one single dominant epitope emerges from the immunization of H−2^k mice with the whole protein of moth cytochrome c (MCC) or closely related pigeon cytochrome c (PCC) (Hedrick et al., 1982; Winoto et al., 1986; Hedrick et al., 1988; McHeyzer-Williams and Davis, 1995). Also, the MCC- or PCC-stimulated CD4⁺ T cell response shows highly organized immunodominance hierarches. The MCC- or PCC-specific responses are highly dominated by Vα11⁺ TCR, and exhibit several conserved CDR3 features (Winoto et al., 1986; Hedrick et al., 1988; McHeyzer-Williams and Davis, 1995; McHeyzer-Williams et al., 1999; Mikszta et al., 1999; Newell et al., 2011). During MCC-specific responses, the Vα11⁺Vβ3⁺ CD4⁺ T cells are the most dominant responders, while Vα11⁺ TCRs pairing with Vβ6⁺, Vβ8⁺, or Vβ14⁺ are the subdominant responders (Miyazaki et al., 1996; Malherbe et al., 2004). Based on the structural data, certain positions at CDR3α and CDR3β regions, where TCR make contact with MCC peptide, present highly conserved amino acid usages (McHeyzer-Williams et al., 1999; Newell et al., 2011). These features constitute the strength of utilizing cytochrome c as a model antigen to study CD4⁺ immunodominance. Moreover, the MCC/I-E^k tetramers have been shown to be able to detect most primary MCC-specific T cells (Savage et al., 1999). Importantly, our laboratory had previously identified a naturally occurring positively selecting self-peptide, termed gp250, for its ability to positively select the MCC-specific TCR: AND (Lo et al., 2009). In this study, we have generated a transgenic mouse line, the gp250 single chain (SC) mouse, in which the gp250/I-E^k was the only MHC class II ligand presented. Combining MCC tetramer analysis and our gp250 SC mice permitted us to elucidate the relationship between positively selecting ligands and antigen specificities of post-selection CD4⁺ T cell repertoires.

Several studies have attempted to investigate the antigen specificities of the post-selection T cell repertoire by limiting the diversity of positively selecting self-peptides (Kouskoff et al., 1993; Ignatowicz et al., 1996; Miyazaki et al., 1996; Fukui et al., 1997; Grubin et al., 1997; Ignatowicz et al., 1997; Nakano et al., 1997; Surh et al., 1997; Tourne et al., 1997; Gapin et al., 1998; Barton and Rudensky, 1999; Chmielowski et al., 2000; Barton et al., 2002; Huseby et al., 2005). Studies that limit the diversity of positively selecting self-peptides to a single peptide have involved the introduction of a transgene that encoded a defined peptide covalently linked to MHC class II (Ignatowicz et al., 1996, 1997; Liu et al., 1997; Huseby et al., 2005), disruption of the peptide exchange molecules H-2M (Miyazaki et al., 1996; Grubin et al., 1997; Surh et al., 1997; Tourne et al., 1997), expression of a human invariant chain transgene in which CLIP peptide was replaced with other self-peptides (Barton and Rudensky, 1999; Barton et al., 2002), or viral expression of altered peptide ligands in the thymus (Kouskoff et al., 1993; Nakano et al., 1997). Altogether these studies concluded that a single peptide could select a large repertoire of T cells and that the recognition of positively selecting ligands is the driving force behind determining the antigen specificities of post-selection T cell repertoire (Ignatowicz et al., 1996; Fukui et al., 1997; Grubin et al., 1997; Ignatowicz et al., 1997; Surh et al., 1997; Fukui et al., 1998; Gapin et al., 1998; Barton and Rudensky, 1999; Chmielowski et al., 2000; Barton et al., 2002; Huseby et al., 2005). However, these studies were unable to examine immunodominance because they did not utilize a naturally occurring positively selecting ligand for a defined foreign antigen.

The selection of Vα11⁺Vβ3⁺ TCRs was greatly enhanced in our gp250 SC mice. CDR3 sequencing revealed that gp250 skewed the positive selection toward MCC-reactive conserved CDR3 features, especially those CDR3s with serine at α91 and asparagine at β97. Our hypothesis that gp250 favors the positive selection of MCC-reactive T cells was further supported by the greatly expanded MCC-tetramer⁺ population in gp250 SC mice. Our data provide direct evidence that positive selection plays a central role in determining the post-selection T cell repertoire and is a major determinant in immunodominance.

Immunodominance describes a common phenomenon of T cell immune responses. Yet the role of positive selection in immunodominance has not been established. In this study, we reported that CD4⁺ T cells specific for a defined antigen are positively selected by a common self-peptide. The self-peptide gp250 positively selected AND TCR, supporting our previous in vitro study (Lo and Allen, 2013), and also selected many other TCRs that have been reported as good MCC responders (Hedrick et al., 1988; McHeyzer-Williams et al., 1999). Our data reveal for the first time that positive selection may influence the TCR V(D)J preference and specific CDR3 junction sequences, and thus shape T cell response to a specific antigen. Our studies therefore offer direct evidence and a new perspective on how to generate a post-selection CD4⁺ T cell repertoire with desired antigen specificities, through engineering the positively selecting self-peptide.

The gp250-selected CD4⁺ T cell repertoire analysis uncovered several very interesting results regarding the specificity of recognizing a positively selecting self-peptide, as well as the relationship between a positively selecting self-peptide and post-selection T cells. In the bulk population TCR repertoire analysis, the CDR3α was found for the well-characterized AND, 5c.c7 and 226 TCRs and also for the majority of published MCC-preferred clones. These findings suggested that one selecting ligand can select as many CDR3s with conserved features for specific antigen recognition as a full self-peptide repertoire could select. Previously, the Davis laboratory and we have shown in vitro that the self-peptide for AND and 5c.c7 TCRs were mutually exclusive with each other (Ebert et al., 2009; Lo and Allen, 2013). The basis for why 5c.c7 was selected in vivo but not in vitro by gp250 probably reflects the relative inefficiency of the in vitro positively selecting assays. Our data suggest these strong MCC-reactive TCR clones may share a common positively selecting ligand, and support our hypothesis that positive selection may be the foundation of T cell immunodominance.

Our finding that gp250 was sufficient to generate a reduced but still a large number of mature CD4⁺ T cells, with a full but skewed range of TCR usages, was similar to the observations in other single peptide mice, such as Eα-, CD22-, or Rab-mediated positive selection (Ignatowicz et al., 1996, 1997; Barton and Rudensky, 1999; Barton et al., 2002) (Figure 7). However, in those previously published studies, the specificity of post-selection repertoire was only examined at a cursorily level by stimulating the CD4⁺ T cells with random known antigens. The gp250 SC mice, however, successfully provided some key insights toward the relationship between positively selecting self-peptide and post-selection CD4⁺ T cells. Thanks to the well-studied MCC polyclonal T cell responses, we were thus able to discover some unique features of positive selection (McHeyzer-Williams and Davis, 1995; McHeyzer-Williams et al., 1999; Mikszta et al., 1999; Malherbe et al., 2004). We found positively selecting self-peptide may favor some unique CDR3 features, which may serve as a good primary and memory responder toward a specific antigen in the periphery.

Consistent with previous studies, the gp250 peptide was able to select a large number of CD4⁺ T cells. This observation makes sense when one considers that the number of selecting self-peptides presented in cortical thymic epithelial cells is smaller than the size of mature CD4⁺ T cell repertoire (Lo and Allen, 2013). Therefore, one positively selecting self-peptide has to select a large number of CD4⁺ T cell with diverse, unrelated antigen specificities, to be able to generate a full CD4⁺ T cell repertoire. The thymic development of regulatory T cells is also dependent upon self-peptides, and requires the strong interaction with these self-peptide MHC ligands (Gottschalk et al., 2010; Ohkura and Sakaguchi, 2010; Corse et al., 2011; Ohkura et al., 2013). However, our preliminary analysis of CD25 expression of CD4SP in the gp250 SC mice did not reveal any significant differences from B6.K mice. The comparable regulatory T cell frequencies in gp250 SC mice and B6.K mice suggested that merely altering the self-peptide diversity was not sufficient to manipulate the affinity threshold for regulatory T cell selection. The finding was perhaps not surprising, given the potential TCR diversity through CDR3 recombination mechanism is nearly infinite, and both the TCR and the self-peptide determine the strength of interaction.

Our data showed gp250 could select many different Vα11 TCRs. How could a peptide influence the selection of many different Vα chains, with a range of CDR3α sequences? The general binding mode of TCR to pMHC has the CDR1 and CDR2 contacting the MHC, and the CDR3 contacting the peptide. One explanation comes from the crystal structure of the 226 TCR bound to MCC/I-E^k28. The side chain of the Arg29 residue of the Vα11 CDR1 makes a hydrogen bond with the backbone carbonyl oxygen of the P3 residue (Newell et al., 2011). Thus gp250 could position the P3 carbonyl oxygen ideally to form this hydrogen bond, and thus favoring Vα11 TCRs. Further structural studies will be needed to reveal the molecular basis of how a single peptide can select defined TCRs.

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Author details

1. Wan-Lin Lo

   Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, United States

   Contribution

   W-LL, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Benjamin D Solomon

   Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, United States

   Contribution

   BDS, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. David L Donermeyer

   Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, United States

   Contribution

   DLD, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Chyi-Song Hsieh

   Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, United States

   Contribution

   C-SH, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

5. Paul M Allen

   Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, United States

   Contribution

   PMA, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   pallen@wustl.edu

   Competing interests

   The authors declare that no competing interests exist.

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