How HLA influences T-cell repertoires and disease

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    Classic major histocompatibility complex (MHC) proteins, also known as human leukocyte antigen (HLA) proteins in humans, play an essential role in immune function and regulation, including influencing the composition of the T-cell repertoire. A growing body of research shows that a range of diseases, including autoimmune diseases, are linked to specific HLA alleles, suggesting that HLA type plays a role in disease susceptibility. (1)

    To understand how HLA type may affect disease, it is crucial to understand the role of these proteins in the adaptive immune system.

    What are HLA proteins?

    HLA proteins are encoded by the MHC—a large gene complex of more than 200 genes. (2)

    HLA proteins fall into two classes:

    1. HLA class I proteins are found on all nucleated cells to different degrees. They present intracellular antigens to the T-cell receptor (TCR) of CD8+ T cells. (3) There are three main HLA types within this class encoded by the HLA-A, HLA-B, and HLA-C loci.
    2. HLA class II proteins are limited to professional antigen-presenting cells. They interact with and activate CD4+ T cells. (3) The three main types of HLA in class II are encoded by the HLA-DR, HLA-DQ, and HLA-DP loci.

    There are also minor HLA loci within HLA class I (HLA-E, HLA-F, and HLA-G) and HLA class II (HLA-DM and HLA-DO).

    These HLA loci are highly polymorphic, with over 30,000 alleles identified to date. HLA-B alone has over 8000 alleles. (4)

    HLA proteins play a critical role in antigen presentation and T-cell activation via their interaction with TCRs (Figure 1).

    HLA and disease

    Figure 1. Representation of HLA proteins presenting an antigen to a T cell through interaction with the TCR. HLA: human leukocyte antigen. Adapted from the Colgate Virology (and Immunology) Blog. (5)

    Understanding HLA type

    An individual’s HLA type is determined by the combination of their different alleles at the major and minor HLA loci. For each locus, an individual can be heterozygous (has two different alleles) or homozygous (has two of the same allele). The presence of multiple HLA loci, each with a large number of alleles, means that the possible number of different HLA types is vast.

    However, some alleles are much more common than others. For example, one study found the HLA allele HLA-A*02 in ~21–27% of individuals analyzed. (6) In addition, some HLA alleles have been found to be more prevalent in certain subpopulations. (6)

    What is the role of HLA proteins in the adaptive immune system?

    The most notable role of HLA proteins in the human immune system is T-cell activation via antigen presentation (see Figure 1). However, HLA proteins also play a role in T-cell development and selection, thereby influencing the T-cell repertoire.

    The role of HLA in T-cell selection in the thymus

    T cells develop from hematopoietic stem cells in the thymus where they undergo many changes, including VDJ recombination and positive or negative selection. (7,8)

    Positive selection ensures that only developing T cells that can bind HLA molecules are selected for further maturation. These may eventually leave the thymus as mature T cells, while T cells that cannot interact with HLA molecules die by neglect (Figure 2). (9) Positive selection also determines whether a T cell becomes a CD4+ or a CD8+ T cell, depending on whether its successful interaction is with an HLA class II or HLA class I protein, respectively.

    Developing T cells in the thymus are also subject to negative selection. There are multiple proposed models of how negative selection occurs, the end result, however, is the deletion of T cells that recognize and bind self antigens (Figure 2). (7)

    HLA and disease

    Figure 2. How interaction between TCR and HLA–peptide complexes shape the T-cell repertoire. HLA: human leukocyte antigen; TCR: T-cell receptor. Adapted from Goldrath et al. (8)

    Therefore, HLA proteins play an essential role in both the positive and negative selection of T cells in the thymus, shaping the resulting T-cell repertoire.

    How does HLA type impact autoimmune disease?

    The link between HLA and autoimmune disease is well characterized and some HLA alleles are linked to an increased risk of several autoimmune disorders (Table 1). For example, HLA-DR4 is linked to an increased risk of developing multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis. (1)

    Table 1. Associations between HLA alleles and autoimmune diseases

    HLA alleleDiseaseImpactReferences
    HLA-DR13, HLA-DR4, HLA-DR15MSIncreases risk(10)
    HLA-A*02:01, HLA-DR4, HLA-DQ8, HLA-DQ2Type 1 diabetesIncreases risk(12–14)
    HLA-DQ2.5 and HLA-DQ8, HLA-DQ2Celiac diseaseIncreases risk(15–17)
    HLA-D4Rheumatoid arthritisIncreases risk(16)
    HLA-Cw6PsoriasisIncreases risk(18)

    HLA type may affect the risk of developing autoimmune disorders by influencing the escape of autoreactive T cells from the thymus. Multiple mechanisms are thought to influence how this may occur, including low autoantigen density and alternate binding of the HLA–peptide–TCR complex. (1)

    The role of autoreactive T cells in the development of autoimmune disease has been confirmed by the identification of such cells in multiple diseases, including type 1 diabetes, where T cells reactive to insulin have been identified (19,20), and MS. (21)

    HLA and non-autoimmune disease: what we know

    Autoimmune diseases are not the only links to specific HLA types. Links between HLA type and susceptibility to other diseases, including cancer and infectious diseases, are known. In addition, HLA type can influence response to treatment, including organ transplant.

    HLA and cancer

    The divergent allele advantage hypothesis dictates that an HLA genotype in which two alleles are more divergent (i.e., have less sequence similarity) allows the presentation of a greater number and diversity of antigens. Higher heterozygosity in HLA genes has been linked to better response to anti-cancer treatments such as immune checkpoint inhibitors (ICIs). (22)

    To further study the association between HLA gene diversity and response to cancer treatment, Chowell et al. investigated the correlation between HLA evolutionary divergence (HED) and outcomes in subjects treated with ICIs. They showed that a higher degree of HED was associated with a higher likelihood of response and longer survival following ICI treatment in subjects with metastatic melanoma and non-small cell lung cancer (Figure 3). (23)

    HLA and disease

    Figure 3. Association of HED with (A) response to ICI treatment and (B) intratumoral TCR clonality. CDR3: complementarity-determining region 3; HED: HLA evolutionary divergence; OR: odds ratio; TCR: T-cell receptor. Adapted from Chowell et al. (23)

    An analysis of immunoSEQ® Data showed a positive correlation between higher HED and intratumoral T-cell clonality, suggesting that HED may increase the likelihood of tumor antigen recognition by tumor-infiltrating T cells, as indicated by the clonal expansion of T cells. (23)

    Read our recent blog post on immunosequencing methods for more information on how immunosequencing and the immunoSEQ Assay works.

    HLA and transplant

    The importance of HLA in transplant is well documented, given that the MHC molecules were named based on their role in transplant rejection. (24)

    However, more research is needed to fully understand how HLA type influences organ rejection. In hematopoietic cell transplant (HCT), there is a known association with permissive mismatches in HLA-DPB1 and improved outcome vs. non-permissive mismatches, but the underlying mechanism is unclear. (25)

    Meurer et al. (26) investigated this phenomenon using various techniques, including the immunoSEQ Assay. They found that permissive mismatches display higher peptide repertoire overlaps and lower frequency and diversity of alloreactive TCRB clonotypes. (26) Figure 4 summarizes the outcomes of this study.

    Figure 4. Mechanisms underlying the improved outcomes in permissive vs. non-permissive HLA-DBP1 mismatches in HCT. HCT: hematopoietic cell transplant; HLA: human leukocyte antigen. Adapted from Walz. (27)

    Understanding how permissive mismatches result in improved outcomes can help to improve donor selection and impact future treatment approaches. (27)

    HLA and infectious diseases

    Chlamydia trachomatis

    Previous research has indicated a relationship between particular HLA-II alleles and outcomes of infection with C. trachomatis, including tubal factor infertility. (28) The severe complications that can arise from C. trachomatis infection make it vital to research the underlying mechanisms of the disease to allow the development of preventative measures and effective treatments.

    Recent research has identified 16 HLA alleles associated with outcomes following C. trachomatis infection. (29) This research also identified immunogenic peptides that could be used to develop diagnostic tools and treatments, including effective vaccines. This highlights the importance of analyzing HLA types when investigating infectious diseases and the associated immune responses.

    Inferring HLA type from immunosequencing

    We have seen how HLA type can influence and shape the T-cell repertoire. Emerson et al. hypothesized that if HLA type influences the composition of the T-cell repertoire, then it might be possible to infer HLA type from immunosequencing data. The authors used the immunoSEQ Assay to sequence the complementarity-determining region 3 (CDR3) of the TCRB gene in a cohort of 666 healthy bone marrow donors. Using this information, they identified 15,601 HLA-allele-associated sequences. The authors used this information to develop models to infer the presence of HLA alleles, paving the way to infer HLA type from immunosequencing data (Figure 5). (30)

    Figure 5. Performance of the various HLA models. A, B, C, DP, DQ, and DR each show information for discrete HLA models sorted by performance. Models with the most data (i.e., alleles that are more common) performed better. (30)

    This research shows the potential to infer HLA type from immunoSEQ Data and has provided insight into how HLA type shapes the T-cell repertoire. The overwhelming majority of the 15,601 HLA-allele-associated sequences were positively associated, with just 87 negative associations. The authors recognize that this requires further investigation, but it could indicate that negative selection is rarer than positive selection. (30)

    The immunoSEQ HLA Classifier

    The above research (30) underpins the recently launched immunoSEQ HLA Classifier, which can infer a sample’s HLA type based on the TCR profile.

    The HLA Classifier compares TCR sequences found in a sample to a database of TCRs known to be associated with a certain HLA type. It runs hundreds of models to infer the HLA alleles most likely expressed in the sample.

    The insights researchers gain from the HLA Classifier can enable them to study a sample’s immune repertoire in the context of HLA type, and assess the role HLA plays in the susceptibility to or protection from disease.

    Discover more about the immunoSEQ HLA Classifier and how it may help propel your research, here.

    How immunosequencing can help our understanding of the role of HLA in disease

    The role of HLA in both autoimmune and non-autoimmune diseases has been highlighted above. Although additional investigations into how HLA affects disease are needed, current evidence suggests that it may be mediated, at least in part, through T-cell responses.

    The immunoSEQ Assay is a cost-effective, user-friendly technology that allows researchers to gain detailed insight into the T- and B-cell repertoires. Using the immunoSEQ Assay in combination with the free immunoSEQ Analyzer platform, T-cell and B-cell responses can be monitored over time and in response to treatment to gain in-depth insight into the role of T cells in disease, as well as the influence of HLA on disease susceptibility and progression.

    We’re here to help you accelerate your research. If you’d like more information, visit our immunoSEQ Assay products page. If you have questions about how to get started, please get in touch with our product team.

    ImmunoSEQ is For Research Use Only. Not for use in diagnostic procedures.


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