A major histocompatibility complex (MHC) class II molecule that binds the same viral pathogen peptide with both nonamer and decamer core sequences for presentation to T cells

Why I Picked This Preprint

As a graduate student in Infectious Diseases and One Health, I chose to highlight the novel findings in this preprint on structural and molecular host-pathogen interactions between chickens and Marek’s Disease Virus (MDV), which contribute to chickens’ resistance to the disease. The impact of this work extends beyound chicken’s immunity as it advances our broader knowledge of virulence and resistance, and supports the One Health approach by providing models for similar viral diseases affecting other species.

Background

Infectious diseases, such as Marek Disease Virus (MDV), Influenza, Newcastle Disease Virus (NDV), are a primary cause of economic loss in poultry farming¹. As can be observed in all viral hosts, the chicken immune system has been evolving new structural and molecular mechanisms to resist these diseases²³. Intriguingly, chicken Major Histocompatibility Complex (MHC) polymorphism shows relatively strong associations with infectious diseases’ peptide fragments compared to mammals, which facilitate resistance to MDV⁴.

Key Findings

• Plasticity in Peptide Binding by Chicken MHC Class II (BL2*021:01)

Chickens have a special immune protein (BL2*021:01) that can present the same viral peptide to two distinct binding motifs on the MHC. As illustrated in preprint Figures 2 to 4, the MHC class II MDV-resistant B21 haplotype can present peptide pp38 through the nonamer core and a decamer core. Specifically, preprint Figure 3 clearly showed the structural comparison of chicken and human MHC class II complexes, revealing unique features in peptide presentation that may underlie enhanced MDV resistance in BL2*021:01.

Figure 3: Representative configurations of peptide–MHC class II complexes from chickens (BL2*021:01, BL2*02:01, BL2*019:01) and humans (HLA-DR1), emphasising the associated antigenic peptides. The surface groove and the distance between anchor residues (P1 to P9 or P10) are displayed for each complex.  Varied orientations and peptide interactions across MHC molecules demonstrate disparities in antigen presentation relevant to resistance to Marek’s Disease Virus (MDV).

This plasticity is unusual during antigenic peptide presentation: usually there are only weak MHC-peptide bonds between mammals and infectious diseases. The ability of BL2*021:01 to bind one peptide to two separate conformations portrays a clear picture of the diversity of molecular surface markers presented to CD4+ T cells in chickens. During clonal expansion of T cells, this plasticity may enhance the number of clones activated by a single peptide to drive resistance. This is also a possible explanation for the high frequency of the B21 haplotype among commercial chickens, as they can survive the wrath of infectious diseases, specifically MDV, in poultries and reach the market.

• Structural Basis for Divergent Peptide Binding Modes

The structural comparison of the BL2*021:01 molecule with the B2 haplotype decamer core motif that is associated with resistance to MDV infection in chickens (BLB*02:01 B2), susceptible BL2*19:01 B19, and human HLA-DR1 counterparts reveals distinct differences within the peptide-binding groove that govern peptide interaction and disease outcome. Specifically, variations in key amino acid residues within the BLB chain modify the local groove architecture, promoting a unique decameric (10-amino-acid core) peptide binding mode. This conformation arises from a subtle “crinkle” or distortion in the peptide backbone at defined positions, dictated by polymorphic contacts between the peptide and the MHC binding pockets. These structural adjustments describe molecular determinants underlying resistance or susceptibility phenotypes.

The crystallographic analysis confirms that this decameric core configuration is not an artefact of crystal packing or monomer associations, which is an important point for understanding the underlying molecular mechanism of chicken resistance to MDV.  To support this even more,  a thorough analysis of intermolecular interactions among various crystal forms (illustrated in preprint Figures 7 and 8) indicate that the identified plasticity binding pattern observed in BL2*021:01 represents a true biological characteristic, emphasising the inherent flexibility and adaptability of the class II peptide-binding groove to accommodate diverse peptide conformations.

Key Contributions

• Chicken MHC decameric core sequence: This preprint has for the first time revealed that chicken MHC II simultaneously binds MDV peptide to a 10-amino-acid core and the classical 9 amino-acid core that resist the MDV by enhancing T lymphocytes response during host-pathogen interaction.
• These findings present a novel MHC architecture in chickens that could inform future research on other infectious diseases like avain influenza, infectious bronchitis virus, Newcastle Disease Virus, etc, antigenic presentation within chickens.

Questions and Future Directions

While this preprint presents novel knowledge in MHC biology, there are further questions that still need to be answered to direct future research. Just a few of these questions are:

1. Can the plasticity property of the B21 haplotype be transferred or induced in susceptible chicken cell lines through manipulation or other cellular and molecular means?
2. During the immune response, what is the functional significance of presenting the same peptide to the nonamer core and a decamer core for T cell clonal expansion and activation?
3. Is this Chicken’s MHC plasticity only specific to MDV? If not, what other infectious dieases undergo this process during peptide presentation and why is this not driving resistance?

 Bibliography

1. Muñoz-Gómez, V. et al. Economic impact of chicken diseases and other causes of morbidity or mortality in backyard farms in low-income and middle-income countries: a systematic review and meta-analysis. BMC Vet Res 21, 151 (2025).
2. Golpasand, S., Ghovvati, S. & Pezeshkian, Z. Exploring the molecular and biological mechanisms of host response in chickens infected with highly pathogenic avian influenza virus (H5N1): An integrative transcriptomic analysis. PLoS One 20, e0332689 (2025).
3. Berihulay, H. et al. Exploring the genetic basis of Newcastle disease virus in chickens: a comprehensive review. Front. Immunol. 16, 1614794 (2025).
4. Kaufman, J. Generalists and Specialists: A New View of How MHC Class I Molecules Fight Infectious Pathogens. Trends in Immunology 39, 367–379 (2018).

Tags: host-pathogen interaction, mdv resistance, mhc class ii

doi: https://doi.org/10.1242/prelights.42027

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